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Find video protocols related to scientific articles indexed in Pubmed.
Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.
Jodie N Painter, Tracy A O'Mara, Jyotsna Batra, Timothy Cheng, Felicity A Lose, Joe Dennis, Kyriaki Michailidou, Jonathan P Tyrer, Shahana Ahmed, Kaltin Ferguson, Catherine S Healey, Susanne Kaufmann, Kristine M Hillman, Carina Walpole, Leire Moya, Pamela Pollock, Angela Jones, Kimberley Howarth, Lynn Martin, Maggie Gorman, Shirley Hodgson, , Ma Magdalena Echeverry de Polanco, Monica Sans, Angel Carracedo, Sergi Castellvi-Bel, Augusto Rojas-Martinez, Erika Santos, Manuel R Teixeira, Luis Carvajal-Carmona, Xiao-Ou Shu, Jirong Long, Wei Zheng, Yong-Bing Xiang, Grant W Montgomery, Penelope M Webb, Rodney J Scott, Mark McEvoy, John Attia, Elizabeth Holliday, Nicholas G Martin, Dale R Nyholt, Anjali K Henders, Peter A Fasching, Alexander Hein, Matthias W Beckmann, Stefan P Renner, Thilo Dörk, Peter Hillemanns, Matthias Dürst, Ingo Runnebaum, Diether Lambrechts, Lieve Coenegrachts, Stefanie Schrauwen, Frédéric Amant, Boris Winterhoff, Sean C Dowdy, Ellen L Goode, Attila Teoman, Helga B Salvesen, Jone Trovik, Tormund S Njolstad, Henrica M J Werner, Katie Ashton, Tony Proietto, Geoffrey Otton, Gerasimos Tzortzatos, Miriam Mints, Emma Tham, Per Hall, Kamila Czene, Jianjun Liu, Jingmei Li, John L Hopper, Melissa C Southey, Arif B Ekici, Matthias Ruebner, Nicola Johnson, Julian Peto, Barbara Burwinkel, Frederik Marme, Hermann Brenner, Aida K Dieffenbach, Alfons Meindl, Hiltrud Brauch, Annika Lindblom, Jeroen Depreeuw, Matthieu Moisse, Jenny Chang-Claude, Anja Rudolph, Fergus J Couch, Janet E Olson, Graham G Giles, Fiona Bruinsma, Julie M Cunningham, Brooke L Fridley, Anne-Lise Børresen-Dale, Vessela N Kristensen, Angela Cox, Anthony J Swerdlow, Nicholas Orr, Manjeet K Bolla, Qin Wang, Rachel Palmieri Weber, Zhihua Chen, Mitul Shah, Juliet D French, Paul D P Pharoah, Alison M Dunning, Ian Tomlinson, Douglas F Easton, Stacey L Edwards, Deborah J Thompson, Amanda B Spurdle.
Hum. Mol. Genet.
PUBLISHED: 11-08-2014
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Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1,184 genotyped and imputed SNPs in 6,608 Caucasian cases and 37,925 controls, and 895 Asian cases and 1,968 controls, revealed the best signal of association for SNP rs11263763 (P=8.4×10(-14), OR=0.86, 95% CI=0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumour samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high to moderate LD as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.
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Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.
Paolo Peterlongo, Jenny Chang-Claude, Kirsten B Moysich, Anja Rudolph, Rita K Schmutzler, Jacques Simard, Penny Soucy, Rosalind A Eeles, Douglas F Easton, Ute Hamann, Stefan Wilkening, Bowang Chen, Matti A Rookus, Marjanka K Schmidt, Frederieke H van der Baan, Amanda B Spurdle, Logan C Walker, Felicity Lose, Ana-Teresa Maia, Marco Montagna, Laura Matricardi, Jan Lubiński, Anna Jakubowska, Encarna B Gomez-Garcia, Olufunmilayo I Olopade, Robert L Nussbaum, Katherine L Nathanson, Susan M Domchek, Timothy R Rebbeck, Banu K Arun, Beth Y Karlan, Sandra Orsulic, Jenny Lester, Wendy K Chung, Alex Miron, Melissa C Southey, David E Goldgar, Saundra S Buys, Ramunas Janavicius, Cecelia M Dorfling, Elizabeth J van Rensburg, Yuan Chun Ding, Susan L Neuhausen, Thomas V O Hansen, Anne-Marie Gerdes, Bent Ejlertsen, Lars Jønson, Ana Osorio, Cristina Martinez-Bouzas, Javier Benitez, Edye E Conway, Kathleen R Blazer, Jeffrey N Weitzel, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Giulietta Scuvera, Monica Barile, Filomena Ficarazzi, Frederique Mariette, Stefano Fortuzzi, Alessandra Viel, Giuseppe Giannini, Laura Papi, Aline Martayan, Maria Grazia Tibiletti, Paolo Radice, Athanassios Vratimos, Florentia Fostira, Judy E Garber, Alan Donaldson, Carole Brewer, Claire Foo, D Gareth R Evans, Debra Frost, Diana Eccles, Angela Brady, Jackie Cook, Marc Tischkowitz, Julian Adlard, Julian Barwell, Lisa Walker, Louise Izatt, Lucy E Side, M John Kennedy, Mark T Rogers, Mary E Porteous, Patrick J Morrison, Radka Platte, Rosemarie Davidson, Shirley V Hodgson, Steve Ellis, Trevor Cole, Andrew K Godwin, Kathleen Claes, Tom Van Maerken, Alfons Meindl, Andrea Gehrig, Christian Sutter, Christoph Engel, Dieter Niederacher, Doris Steinemann, Hansjoerg Plendl, Karin Kast, Kerstin Rhiem, Nina Ditsch, Norbert Arnold, Raymonda Varon-Mateeva, Barbara Wappenschmidt, Shan Wang-Gohrke, Brigitte Bressac-de Paillerets, Bruno Buecher, Capucine Delnatte, Claude Houdayer, Dominique Stoppa-Lyonnet, Francesca Damiola, Isabelle Coupier, Laure Barjhoux, Laurence Venat-Bouvet, Lisa Golmard, Nadia Boutry-Kryza, Olga M Sinilnikova, Olivier Caron, Pascal Pujol, Sylvie Mazoyer, Muriel Belotti, Marion Piedmonte, Michael L Friedlander, Gustavo C Rodriguez, Larry J Copeland, Miguel de la Hoya, Pedro Perez Segura, Heli Nevanlinna, Kristiina Aittomäki, Theo A M van Os, Hanne E J Meijers-Heijboer, Annemarie H Van der Hout, Maaike P G Vreeswijk, Nicoline Hoogerbrugge, Margreet G E M Ausems, Helena C Van Doorn, J Margriet Collée, Edith Olah, Orland Díez, Ignacio Blanco, Conxi Lazaro, Joan Brunet, Lídia Feliubadaló, Cezary Cybulski, Jacek Gronwald, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Grzegorz Sukiennicki, Adalgeir Arason, Jocelyne Chiquette, Manuel R Teixeira, Curtis Olswold, Fergus J Couch, Noralane M Lindor, Xianshu Wang, Csilla I Szabo, Kenneth Offit, Marina Corines, Lauren Jacobs, Mark Robson, Liying Zhang, Vijai Joseph, Andreas Berger, Christian F Singer, Christine Rappaport, Daphne Geschwantler Kaulich, Georg Pfeiler, Muy-Kheng M Tea, Catherine M Phelan, Mark H Greene, Phuong L Mai, Gad Rennert, Anna Marie Mulligan, Gord Glendon, Sandrine Tchatchou, Irene L Andrulis, Amanda Ewart Toland, Anders Bojesen, Inge Sokilde Pedersen, Mads Thomassen, Uffe Birk Jensen, Yael Laitman, Johanna Rantala, Anna von Wachenfeldt, Hans Ehrencrona, Marie Stenmark Askmalm, Ake Borg, Karoline B Kuchenbaecker, Lesley McGuffog, Daniel Barrowdale, Sue Healey, Andrew Lee, Paul D P Pharoah, Georgia Chenevix-Trench, Antonis C Antoniou, Eitan Friedman.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 10-23-2014
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Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
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Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.
Wei-Yu Lin, Nicola J Camp, Maya Ghoussaini, Jonathan Beesley, Kyriaki Michailidou, John L Hopper, Carmel Apicella, Melissa C Southey, Jennifer Stone, Marjanka K Schmidt, Annegien Broeks, Laura J Van't Veer, Emiel J Th Rutgers, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Peter A Fasching, Lothar Haeberle, Arif B Ekici, Matthias W Beckmann, Julian Peto, Isabel Dos-Santos-Silva, Olivia Fletcher, Nichola Johnson, Manjeet K Bolla, Qin Wang, Joe Dennis, Elinor J Sawyer, Timothy Cheng, Ian Tomlinson, Michael J Kerin, Nicola Miller, Frederik Marme, Harald M Surowy, Barbara Burwinkel, Pascal Guénel, Thérèse Truong, Florence Menegaux, Claire Mulot, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Javier Benitez, M Pilar Zamora, José Ignacio Arias Perez, Primitiva Menéndez, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Nuria Alvarez, Daniel Herrero, Hoda Anton-Culver, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Alfons Meindl, Peter Lichtner, Rita K Schmutzler, Bertram Müller-Myhsok, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, , Daniel C Tessier, Daniel Vincent, Francois Bacot, Heli Nevanlinna, Kristiina Aittomäki, Carl Blomqvist, Sofia Khan, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Akiyo Horio, Natalia V Bogdanova, Natalia N Antonenkova, Thilo Dörk, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Anna H Wu, Chiu-Chen Tseng, David Van Den Berg, Daniel O Stram, Patrick Neven, Els Wauters, Hans Wildiers, Diether Lambrechts, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Bernardo Bonanni, Fergus J Couch, Xianshu Wang, Celine Vachon, Kristen Purrington, Graham G Giles, Roger L Milne, Catriona McLean, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Soo Hwang Teo, Cheng Har Yip, Norhashimah Hassan, Eranga Nishanthie Vithana, Vessela Kristensen, Wei Zheng, Sandra Deming-Halverson, Martha J Shrubsole, Jirong Long, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Irene L Andrulis, Julia A Knight, Gord Glendon, Sandrine Tchatchou, Peter Devilee, Robert A E M Tollenaar, Caroline Seynaeve, Christi J van Asperen, Montserrat Garcia-Closas, Jonine Figueroa, Jolanta Lissowska, Louise Brinton, Kamila Czene, Hatef Darabi, Mikael Eriksson, Judith S Brand, Maartje J Hooning, Antoinette Hollestelle, Ans M W van den Ouweland, Agnes Jager, Jingmei Li, Jianjun Liu, Keith Humphreys, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Hui Cai, Simon S Cross, Malcolm W R Reed, William Blot, Lisa B Signorello, Qiuyin Cai, Paul D P Pharoah, Barbara Perkins, Mitul Shah, Fiona M Blows, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Mikael Hartman, Hui Miao, Kee Seng Chia, Thomas Choudary Putti, Ute Hamann, Craig Luccarini, Caroline Baynes, Shahana Ahmed, Mel Maranian, Catherine S Healey, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Susan Slager, Amanda E Toland, Drakoulis Yannoukakos, Chen-Yang Shen, Chia-Ni Hsiung, Pei-Ei Wu, Shian-Ling Ding, Alan Ashworth, Michael Jones, Nick Orr, Anthony J Swerdlow, Helen Tsimiklis, Enes Makalic, Daniel F Schmidt, Quang M Bui, Stephen J Chanock, David J Hunter, Rebecca Hein, Norbert Dahmen, Lars Beckmann, Kirsimari Aaltonen, Taru A Muranen, Tuomas Heikkinen, Astrid Irwanto, Nazneen Rahman, Clare A Turnbull, Quinten Waisfisz, Hanne E J Meijers-Heijboer, Muriel A Adank, Rob B van der Luijt, Per Hall, Georgia Chenevix-Trench, Alison Dunning, Douglas F Easton, Angela Cox.
Hum. Mol. Genet.
PUBLISHED: 08-28-2014
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Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
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Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade.
Kristen S Purrington, Seth Slettedahl, Manjeet K Bolla, Kyriaki Michailidou, Kamila Czene, Heli Nevanlinna, Stig E Bojesen, Irene L Andrulis, Angela Cox, Per Hall, Jane Carpenter, Drakoulis Yannoukakos, Christopher A Haiman, Peter A Fasching, Arto Mannermaa, Robert Winqvist, Hermann Brenner, Annika Lindblom, Georgia Chenevix-Trench, Javier Benitez, Anthony Swerdlow, Vessela Kristensen, Pascal Guénel, Alfons Meindl, Hatef Darabi, Mikael Eriksson, Rainer Fagerholm, Kristiina Aittomäki, Carl Blomqvist, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Xianshu Wang, Curtis Olswold, Janet E Olson, Anna Marie Mulligan, Julia A Knight, Sandrine Tchatchou, Malcolm W R Reed, Simon S Cross, Jianjun Liu, Jingmei Li, Keith Humphreys, Christine Clarke, Rodney Scott, , Florentia Fostira, George Fountzilas, Irene Konstantopoulou, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Arif B Ekici, Arndt Hartmann, Matthias W Beckmann, Jaana M Hartikainen, Veli-Matti Kosma, Vesa Kataja, Arja Jukkola-Vuorinen, Katri Pylkäs, Saila Kauppila, Aida Karina Dieffenbach, Christa Stegmaier, Volker Arndt, Sara Margolin, Rosemary Balleine, José Ignacio Arias Perez, M Pilar Zamora, Primitiva Menéndez, Alan Ashworth, Michael Jones, Nick Orr, Patrick Arveux, Pierre Kerbrat, Thérèse Truong, Peter Bugert, Amanda E Toland, Christine B Ambrosone, France Labrèche, Mark S Goldberg, Martine Dumont, Argyrios Ziogas, Eunjung Lee, Gillian S Dite, Carmel Apicella, Melissa C Southey, Jirong Long, Martha Shrubsole, Sandra Deming-Halverson, Filomena Ficarazzi, Monica Barile, Paolo Peterlongo, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Robert A E M Tollenaar, Caroline Seynaeve, Thomas Brüning, Yon-Dschun Ko, Carolien H M van Deurzen, John W M Martens, Mieke Kriege, Jonine D Figueroa, Stephen J Chanock, Jolanta Lissowska, Ian Tomlinson, Michael J Kerin, Nicola Miller, Andreas Schneeweiss, William J Tapper, Susan M Gerty, Lorraine Durcan, Catriona McLean, Roger L Milne, Laura Baglietto, Isabel Dos Santos Silva, Olivia Fletcher, Nichola Johnson, Laura J Van't Veer, Sten Cornelissen, Asta Försti, Diana Torres, Thomas Rüdiger, Anja Rudolph, Dieter Flesch-Janys, Stefan Nickels, Caroline Weltens, Giuseppe Floris, Matthieu Moisse, Joe Dennis, Qin Wang, Alison M Dunning, Mitul Shah, Judith Brown, Jacques Simard, Hoda Anton-Culver, Susan L Neuhausen, John L Hopper, Natalia Bogdanova, Thilo Dörk, Wei Zheng, Paolo Radice, Anna Jakubowska, Jan Lubiński, Peter Devillee, Hiltrud Brauch, Maartje Hooning, Montserrat Garcia-Closas, Elinor Sawyer, Barbara Burwinkel, Frederick Marmee, Diana M Eccles, Graham G Giles, Julian Peto, Marjanka Schmidt, Annegien Broeks, Ute Hamann, Jenny Chang-Claude, Diether Lambrechts, Paul D P Pharoah, Douglas Easton, V Shane Pankratz, Susan Slager, Celine M Vachon, Fergus J Couch.
Hum. Mol. Genet.
PUBLISHED: 06-13-2014
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Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.
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Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study.
Nichola Johnson, Frank Dudbridge, Nick Orr, Lorna Gibson, Michael E Jones, Minouk J Schoemaker, Elizabeth J Folkerd, Ben P Haynes, John L Hopper, Melissa C Southey, Gillian S Dite, Carmel Apicella, Marjanka K Schmidt, Annegien Broeks, Laura J Van T Veer, Femke Atsma, Kenneth Muir, Artitaya Lophatananon, Peter A Fasching, Matthias W Beckmann, Arif B Ekici, Stefan P Renner, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Nicola Miller, Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Pascal Guénel, Thérèse Truong, Emilie Cordina, Florence Menegaux, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, Roger Milne, M Pilar Zamora, José Ignacio Arias Perez, Javier Benitez, Leslie Bernstein, Hoda Anton-Culver, Argyrios Ziogas, Christina Clarke Dur, Hermann Brenner, Heiko Muller, Volker Arndt, Aida Karina Dieffenbach, Alfons Meindl, Joerg Heil, Claus R Bartram, Rita K Schmutzler, Hiltrud Brauch, Christina Justenhoven, Yon-Dschun Ko, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Keitaro Matsuo, Thilo Dörk, Natalia V Bogdanova, Natalia N Antonenkova, Annika Lindblom, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Georgia Chenevix-Trench, Jonathan Beesley, Anna H Wu, David Van Den Berg, Chiu-Chen Tseng, Diether Lambrechts, Dominiek Smeets, Patrick Neven, Hans Wildiers, Jenny Chang-Claude, Anja Rudolph, Stefan Nickels, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Valeria Pensotti, Fergus J Couch, Janet E Olson, Xianshu Wang, Zachary Fredericksen, Vernon S Pankratz, Graham G Giles, Gianluca Severi, Laura Baglietto, Chris Haiman, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Penny Soucy, Soo Teo, Cheng Har Yip, Sze Yee Phuah, Belinda K Cornes, Vessela N Kristensen, Grethe Grenaker Alnæs, Anne-Lise Børresen-Dale, Wei Zheng, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Peter Devillee, Jonine Figueroa, Stephen J Chanock, Jolanta Lissowska, Mark E Sherman, Per Hall, Nils Schoof, Maartje Hooning, Antoinette Hollestelle, Rogier A Oldenburg, Madeleine Tilanus-Linthorst, Jianjun Liu, Angie Cox, Ian W Brock, Malcolm Wr Reed, Simon S Cross, William Blot, Lisa B Signorello, Paul Dp Pharoah, Alison M Dunning, Mitul Shah, Daehee Kang, Dong-Young Noh, Sue K Park, Ji-Yeob Choi, Mikael Hartman, Hui Miao, Wei Yen Lim, Anthony Tang, Ute Hamann, Asta Försti, Thomas Rüdiger, Hans Ulrich Ulmer, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Susan Slager, Amanda E Toland, Celine Vachon, Drakoulis Yannoukakos, Chen-Yang Shen, Jyh-Cherng Yu, Chiun-Sheng Huang, Ming-Feng Hou, Anna González-Neira, Daniel C Tessier, Daniel Vincent, Francois Bacot, Craig Luccarini, Joe Dennis, Kyriaki Michailidou, Manjeet K Bolla, Jean Wang, Douglas F Easton, Montserrat Garcia-Closas, Mitch Dowsett, Alan Ashworth, Anthony J Swerdlow, Julian Peto, Isabel Dos Santos Silva, Olivia Fletcher.
Breast Cancer Res.
PUBLISHED: 05-26-2014
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We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age <=50 years.
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Genetic predisposition to in situ and invasive lobular carcinoma of the breast.
Elinor Sawyer, Rebecca Roylance, Christos Petridis, Mark N Brook, Salpie Nowinski, Efterpi Papouli, Olivia Fletcher, Sarah Pinder, Andrew Hanby, Kelly Kohut, Patricia Gorman, Michele Caneppele, Julian Peto, Isabel Dos Santos Silva, Nichola Johnson, Ruth Swann, Miriam Dwek, Katherine-Anne Perkins, Cheryl Gillett, Richard Houlston, Gillian Ross, Paolo De Ieso, Melissa C Southey, John L Hopper, Elena Provenzano, Carmel Apicella, Jelle Wesseling, Sten Cornelissen, Renske Keeman, Peter A Fasching, Sebastian M Jud, Arif B Ekici, Matthias W Beckmann, Michael J Kerin, Federick Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Pierre Kerbrat, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Roger L Milne, Jose Ignacio Arias Perez, Primitiva Menéndez, Javier Benitez, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Alfons Meindl, Peter Lichtner, Rita K Schmutzler, Magdalena Lochmann, Hiltrud Brauch, Hans-Peter Fischer, Yon-Dschun Ko, , Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Natalia V Bogdanova, Thilo Dörk, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Georgia Chenevix-Trench, Kconfab Investigators, Diether Lambrechts, Caroline Weltens, Erik Van Limbergen, Sigrid Hatse, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Sara Volorio, Graham G Giles, Gianluca Severi, Laura Baglietto, Catriona A McLean, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Vessela Kristensen, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Peter Devillee, Rob A E M Tollenaar, Caroline M Seynaeve, Mieke Kriege, Jonine Figueroa, Stephen J Chanock, Mark E Sherman, Maartje J Hooning, Antoinette Hollestelle, Ans M W van den Ouweland, Carolien H M van Deurzen, Jingmei Li, Kamila Czene, Keith Humphreys, Angela Cox, Simon S Cross, Malcolm W R Reed, Mitul Shah, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Anthony Swerdlow, Alan Ashworth, Nicholas Orr, Minouk Schoemaker, Fergus J Couch, Emily Hallberg, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Daniel C Tessier, Daniel Vincent, Francois Bacot, Manjeet K Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Alison M Dunning, Per Hall, Doug Easton, Paul Pharoah, Marjanka K Schmidt, Ian Tomlinson, Montserrat Garcia-Closas.
PLoS Genet.
PUBLISHED: 04-01-2014
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Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.
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DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.
Ana Osorio, Roger L Milne, Karoline Kuchenbaecker, Tereza Vaclová, Guillermo Pita, Rosario Alonso, Paolo Peterlongo, Ignacio Blanco, Miguel de la Hoya, Mercedes Durán, Orland Díez, Teresa Ramón Y Cajal, Irene Konstantopoulou, Cristina Martinez-Bouzas, Raquel Andrés Conejero, Penny Soucy, Lesley McGuffog, Daniel Barrowdale, Andrew Lee, Swe-Brca, Brita Arver, Johanna Rantala, Niklas Loman, Hans Ehrencrona, Olufunmilayo I Olopade, Mary S Beattie, Susan M Domchek, Katherine Nathanson, Timothy R Rebbeck, Banu K Arun, Beth Y Karlan, Christine Walsh, Jenny Lester, Esther M John, Alice S Whittemore, Mary B Daly, Melissa Southey, John Hopper, Mary B Terry, Saundra S Buys, Ramunas Janavicius, Cecilia M Dorfling, Elizabeth J van Rensburg, Linda Steele, Susan L Neuhausen, Yuan Chun Ding, Thomas V O Hansen, Lars Jønson, Bent Ejlertsen, Anne-Marie Gerdes, Mar Infante, Belen Herráez, Leticia Thais Moreno, Jeffrey N Weitzel, Josef Herzog, Kisa Weeman, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Giulietta Scuvera, Bernardo Bonanni, Frederique Mariette, Sara Volorio, Alessandra Viel, Liliana Varesco, Laura Papi, Laura Ottini, Maria Grazia Tibiletti, Paolo Radice, Drakoulis Yannoukakos, Judy Garber, Steve Ellis, Debra Frost, Radka Platte, Elena Fineberg, Gareth Evans, Fiona Lalloo, Louise Izatt, Ros Eeles, Julian Adlard, Rosemarie Davidson, Trevor Cole, Diana Eccles, Jackie Cook, Shirley Hodgson, Carole Brewer, Marc Tischkowitz, Fiona Douglas, Mary Porteous, Lucy Side, Lisa Walker, Patrick Morrison, Alan Donaldson, John Kennedy, Claire Foo, Andrew K Godwin, Rita Katharina Schmutzler, Barbara Wappenschmidt, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hans Jörg Plendl, Dieter Niederacher, Christian Sutter, Shan Wang-Gohrke, Doris Steinemann, Sabine Preisler-Adams, Karin Kast, Raymonda Varon-Mateeva, Andrea Gehrig, Dominique Stoppa-Lyonnet, Olga M Sinilnikova, Sylvie Mazoyer, Francesca Damiola, Bruce Poppe, Kathleen Claes, Marion Piedmonte, Kathy Tucker, Floor Backes, Gustavo Rodriguez, Wendy Brewster, Katie Wakeley, Thomas Rutherford, Trinidad Caldés, Heli Nevanlinna, Kristiina Aittomäki, Matti A Rookus, Theo A M van Os, Lizet van der Kolk, J L de Lange, Hanne E J Meijers-Heijboer, A H van der Hout, Christi J van Asperen, Encarna B Gomez Garcia, Nicoline Hoogerbrugge, J Margriet Collée, Carolien H M van Deurzen, Rob B van der Luijt, Peter Devilee, Hebon, Edith Olah, Conxi Lazaro, Alex Teulé, Mireia Menéndez, Anna Jakubowska, Cezary Cybulski, Jacek Gronwald, Jan Lubiński, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Oskar Th Johannsson, Christine Maugard, Marco Montagna, Silvia Tognazzo, Manuel R Teixeira, Sue Healey, Kconfab Investigators, Curtis Olswold, Lucia Guidugli, Noralane Lindor, Susan Slager, Csilla I Szabo, Joseph Vijai, Mark Robson, Noah Kauff, Liying Zhang, Rohini Rau-Murthy, Anneliese Fink-Retter, Christian F Singer, Christine Rappaport, Daphne Geschwantler Kaulich, Georg Pfeiler, Muy-Kheng Tea, Andreas Berger, Catherine M Phelan, Mark H Greene, Phuong L Mai, Flavio Lejbkowicz, Irene Andrulis, Anna Marie Mulligan, Gord Glendon, Amanda Ewart Toland, Anders Bojesen, Inge Sokilde Pedersen, Lone Sunde, Mads Thomassen, Torben A Kruse, Uffe Birk Jensen, Eitan Friedman, Yael Laitman, Shani Paluch Shimon, Jacques Simard, Douglas F Easton, Kenneth Offit, Fergus J Couch, Georgia Chenevix-Trench, Antonis C Antoniou, Javier Benitez.
PLoS Genet.
PUBLISHED: 04-01-2014
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Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
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Validation of the Manchester scoring system for predicting BRCA1/2 mutations in 9,390 families suspected of having hereditary breast and ovarian cancer.
Int. J. Cancer
PUBLISHED: 02-27-2014
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The Manchester scoring system (MSS) allows the calculation of the probability for the presence of mutations in BRCA1 or BRCA2 genes in families suspected of having hereditary breast and ovarian cancer. In 9,390 families, we determined the predictive performance of the MSS without (MSS-2004) and with (MSS-2009) consideration of pathology parameters. Moreover, we validated a recalibrated version of the MSS-2009 (MSS-recal). Families were included in the registry of the German Consortium for Hereditary Breast and Ovarian Cancer, using defined clinical criteria. Receiver operating characteristics (ROC) analysis was used to determine the predictive performance. The recalibrated model was developed using logistic regression analysis and tested using an independent random validation sample. The area under the ROC curves regarding a mutation in any of the two BRCA genes was 0.77 (95%CI 0.75-0.79) for MSS-2004, 0.80 (95%CI 0.78-0.82) for MSS-2009, and 0.82 (95%CI 0.80-0.83) for MSS-recal. Sensitivity at the 10% mutation probability cutoff was similar for all three models (MSS-2004 92.2%, MSS-2009 92.2%, and MSS-recal 90.3%), but specificity of MSS-recal (46.0%) was considerably higher than that of MSS-2004 (25.4%) and MSS-2009 (32.3%). In the MSS-recal model, almost all predictors of the original MSS were significantly predictive. However, the score values of some predictors, for example, high grade triple negative breast cancers, differed considerably from the originally proposed score values. The original MSS performed well in our sample of high risk families. The use of pathological parameters increased the predictive performance significantly. Recalibration improved the specificity considerably without losing much sensitivity.
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A genome-wide association study of early-onset breast cancer identifies PFKM as a novel breast cancer gene and supports a common genetic spectrum for breast cancer at any age.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 02-03-2014
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Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ? 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10(-8)) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10(-4)) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10(-6). In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer.
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MicroRNA Related Polymorphisms and Breast Cancer Risk.
Sofia Khan, Dario Greco, Kyriaki Michailidou, Roger L Milne, Taru A Muranen, Tuomas Heikkinen, Kirsimari Aaltonen, Joe Dennis, Manjeet K Bolla, Jianjun Liu, Per Hall, Astrid Irwanto, Keith Humphreys, Jingmei Li, Kamila Czene, Jenny Chang-Claude, Rebecca Hein, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Olivia Fletcher, Julian Peto, Isabel Dos Santos Silva, Nichola Johnson, Lorna Gibson, Zoe Aitken, John L Hopper, Helen Tsimiklis, Minh Bui, Enes Makalic, Daniel F Schmidt, Melissa C Southey, Carmel Apicella, Jennifer Stone, Quinten Waisfisz, Hanne Meijers-Heijboer, Muriel A Adank, Rob B van der Luijt, Alfons Meindl, Rita K Schmutzler, Bertram Müller-Myhsok, Peter Lichtner, Clare Turnbull, Nazneen Rahman, Stephen J Chanock, David J Hunter, Angela Cox, Simon S Cross, Malcolm W R Reed, Marjanka K Schmidt, Annegien Broeks, Laura J V A N't Veer, Frans B Hogervorst, Peter A Fasching, Michael G Schrauder, Arif B Ekici, Matthias W Beckmann, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Javier Benitez, Pilar M Zamora, Jose I A Perez, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Paul D P Pharoah, Alison M Dunning, Mitul Shah, Robert Luben, Judith Brown, Fergus J Couch, Xianshu Wang, Celine Vachon, Janet E Olson, Diether Lambrechts, Matthieu Moisse, Robert Paridaens, Marie-Rose Christiaens, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Claire Mulot, Frederick Marme, Barbara Burwinkel, Andreas Schneeweiss, Christof Sohn, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Irene L Andrulis, Julia A Knight, Sandrine Tchatchou, Anna Marie Mulligan, Thilo Dörk, Natalia V Bogdanova, Natalia N Antonenkova, Hoda Anton-Culver, Hatef Darabi, Mikael Eriksson, Montserrat Garcia-Closas, Jonine Figueroa, Jolanta Lissowska, Louise Brinton, Peter Devilee, Robert A E M Tollenaar, Caroline Seynaeve, Christi J van Asperen, Vessela N Kristensen, , Susan Slager, Amanda E Toland, Christine B Ambrosone, Drakoulis Yannoukakos, Annika Lindblom, Sara Margolin, Paolo Radice, Paolo Peterlongo, Monica Barile, Paolo Mariani, Maartje J Hooning, John W M Martens, J Margriet Collée, Agnes Jager, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Graham G Giles, Catriona McLean, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Anthony Swerdlow, Alan Ashworth, Nick Orr, Michael Jones, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Arto Mannermaa, Ute Hamann, Georgia Chenevix-Trench, Carl Blomqvist, Kristiina Aittomäki, Douglas F Easton, Heli Nevanlinna.
PLoS ONE
PUBLISHED: 01-01-2014
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Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
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Fine-Scale Mapping of the FGFR2 Breast Cancer Risk Locus: Putative Functional Variants Differentially Bind FOXA1 and E2F1.
Kerstin B Meyer, Martin O'Reilly, Kyriaki Michailidou, Saskia Carlebur, Stacey L Edwards, Juliet D French, Radhika Prathalingham, Joe Dennis, Manjeet K Bolla, Qin Wang, Ines de Santiago, John L Hopper, Helen Tsimiklis, Carmel Apicella, Melissa C Southey, Marjanka K Schmidt, Annegien Broeks, Laura J van 't Veer, Frans B Hogervorst, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Peter A Fasching, Michael P Lux, Arif B Ekici, Matthias W Beckmann, Julian Peto, Isabel Dos Santos Silva, Olivia Fletcher, Nichola Johnson, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Federick Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Florence Menegaux, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Roger L Milne, M Pilar Zamora, Jose I Arias, Javier Benitez, Susan Neuhausen, Hoda Anton-Culver, Argyrios Ziogas, Christina C Dur, Hermann Brenner, Heiko Muller, Volker Arndt, Christa Stegmaier, Alfons Meindl, Rita K Schmutzler, Christoph Engel, Nina Ditsch, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, , Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Yasushi Yatabe, Thilo Dörk, Sonja Helbig, Natalia V Bogdanova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Georgia Chenevix-Trench, Anna H Wu, Chiu-Chen Tseng, David Van Den Berg, Daniel O Stram, Diether Lambrechts, Bernard Thienpont, Marie-Rose Christiaens, Ann Smeets, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Loris Bernard, Fergus J Couch, Janet E Olson, Xianshu Wang, Kristen Purrington, Graham G Giles, Gianluca Severi, Laura Baglietto, Catriona McLean, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Soo-Hwang Teo, Cheng-Har Yip, Sze-Yee Phuah, Vessela Kristensen, Grethe Grenaker Alnæs, Anne-Lise Børresen-Dale, Wei Zheng, Sandra Deming-Halverson, Martha Shrubsole, Jirong Long, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Irene L Andrulis, Julia A Knight, Gord Glendon, Sandrine Tchatchou, Peter Devilee, Robert A E M Tollenaar, Caroline M Seynaeve, Montserrat Garcia-Closas, Jonine Figueroa, Stephen J Chanock, Jolanta Lissowska, Kamila Czene, Hartef Darabi, Kimael Eriksson, Maartje J Hooning, John W M Martens, Ans M W van den Ouweland, Carolien H M van Deurzen, Per Hall, Jingmei Li, Jianjun Liu, Keith Humphreys, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Hui Cai, Angela Cox, Malcolm W R Reed, William Blot, Lisa B Signorello, Qiuyin Cai, Paul D P Pharoah, Maya Ghoussaini, Patricia Harrington, Jonathan Tyrer, Daehee Kang, Ji-Yeob Choi, Sue K Park, Dong-Young Noh, Mikael Hartman, Miao Hui, Wei-Yen Lim, Shaik A Buhari, Ute Hamann, Asta Försti, Thomas Rüdiger, Hans-Ulrich Ulmer, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska, Katarzyna Durda, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Celine Vachon, Susan Slager, Florentia Fostira, Robert Pilarski, Chen-Yang Shen, Chia-Ni Hsiung, Pei-Ei Wu, Ming-Feng Hou, Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk J Schoemaker, Bruce A J Ponder, Alison M Dunning, Douglas F Easton.
Am. J. Hum. Genet.
PUBLISHED: 08-01-2013
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The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ER? to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease.
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Evaluating the performance of the breast cancer genetic risk models BOADICEA, IBIS, BRCAPRO and Claus for predicting BRCA1/2 mutation carrier probabilities: a study based on 7352 families from the German Hereditary Breast and Ovarian Cancer Consortium.
J. Med. Genet.
PUBLISHED: 04-06-2013
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Risk prediction models are widely used in clinical genetic counselling. Despite their frequent use, the genetic risk models BOADICEA, BRCAPRO, IBIS and extended Claus model (eCLAUS), used to estimate BRCA1/2 mutation carrier probabilities, have never been comparatively evaluated in a large sample from central Europe. Additionally, a novel version of BOADICEA that incorporates tumour pathology information has not yet been validated.
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Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.
Fergus J Couch, Xianshu Wang, Lesley McGuffog, Andrew Lee, Curtis Olswold, Karoline B Kuchenbaecker, Penny Soucy, Zachary Fredericksen, Daniel Barrowdale, Joe Dennis, Mia M Gaudet, Ed Dicks, Matthew Kosel, Sue Healey, Olga M Sinilnikova, Adam Lee, Francois Bacot, Daniel Vincent, Frans B L Hogervorst, Susan Peock, Dominique Stoppa-Lyonnet, Anna Jakubowska, , Paolo Radice, Rita Katharina Schmutzler, Susan M Domchek, Marion Piedmonte, Christian F Singer, Eitan Friedman, Mads Thomassen, Thomas V O Hansen, Susan L Neuhausen, Csilla I Szabo, Ignacio Blanco, Mark H Greene, Beth Y Karlan, Judy Garber, Catherine M Phelan, Jeffrey N Weitzel, Marco Montagna, Edith Olah, Irene L Andrulis, Andrew K Godwin, Drakoulis Yannoukakos, David E Goldgar, Trinidad Caldés, Heli Nevanlinna, Ana Osorio, Mary Beth Terry, Mary B Daly, Elizabeth J van Rensburg, Ute Hamann, Susan J Ramus, Amanda Ewart Toland, Maria A Caligo, Olufunmilayo I Olopade, Nadine Tung, Kathleen Claes, Mary S Beattie, Melissa C Southey, Evgeny N Imyanitov, Marc Tischkowitz, Ramunas Janavicius, Esther M John, Ava Kwong, Orland Díez, Judith Balmaña, Rosa B Barkardottir, Banu K Arun, Gad Rennert, Soo-Hwang Teo, Patricia A Ganz, Ian Campbell, Annemarie H Van der Hout, Carolien H M van Deurzen, Caroline Seynaeve, Encarna B Gomez Garcia, Flora E van Leeuwen, Hanne E J Meijers-Heijboer, Johannes J P Gille, Margreet G E M Ausems, Marinus J Blok, Marjolijn J L Ligtenberg, Matti A Rookus, Peter Devilee, Senno Verhoef, Theo A M van Os, Juul T Wijnen, Debra Frost, Steve Ellis, Elena Fineberg, Radka Platte, D Gareth Evans, Louise Izatt, Rosalind A Eeles, Julian Adlard, Diana M Eccles, Jackie Cook, Carole Brewer, Fiona Douglas, Shirley Hodgson, Patrick J Morrison, Lucy E Side, Alan Donaldson, Catherine Houghton, Mark T Rogers, Huw Dorkins, Jacqueline Eason, Helen Gregory, Emma McCann, Alex Murray, Alain Calender, Agnès Hardouin, Pascaline Berthet, Capucine Delnatte, Catherine Noguès, Christine Lasset, Claude Houdayer, Dominique Leroux, Etienne Rouleau, Fabienne Prieur, Francesca Damiola, Hagay Sobol, Isabelle Coupier, Laurence Venat-Bouvet, Laurent Castera, Marion Gauthier-Villars, Mélanie Léoné, Pascal Pujol, Sylvie Mazoyer, Yves-Jean Bignon, Elżbieta Złowocka-Perłowska, Jacek Gronwald, Jan Lubiński, Katarzyna Durda, Katarzyna Jaworska, Tomasz Huzarski, Amanda B Spurdle, Alessandra Viel, Bernard Peissel, Bernardo Bonanni, Giulia Melloni, Laura Ottini, Laura Papi, Liliana Varesco, Maria Grazia Tibiletti, Paolo Peterlongo, Sara Volorio, Siranoush Manoukian, Valeria Pensotti, Norbert Arnold, Christoph Engel, Helmut Deissler, Dorothea Gadzicki, Andrea Gehrig, Karin Kast, Kerstin Rhiem, Alfons Meindl, Dieter Niederacher, Nina Ditsch, Hansjoerg Plendl, Sabine Preisler-Adams, Stefanie Engert, Christian Sutter, Raymonda Varon-Mateeva, Barbara Wappenschmidt, Bernhard H F Weber, Brita Arver, Marie Stenmark-Askmalm, Niklas Loman, Richard Rosenquist, Zakaria Einbeigi, Katherine L Nathanson, Timothy R Rebbeck, Stephanie V Blank, David E Cohn, Gustavo C Rodriguez, Laurie Small, Michael Friedlander, Victoria L Bae-Jump, Anneliese Fink-Retter, Christine Rappaport, Daphne Gschwantler-Kaulich, Georg Pfeiler, Muy-Kheng Tea, Noralane M Lindor, Bella Kaufman, Shani Shimon Paluch, Yael Laitman, Anne-Bine Skytte, Anne-Marie Gerdes, Inge Sokilde Pedersen, Sanne Traasdahl Moeller, Torben A Kruse, Uffe Birk Jensen, Joseph Vijai, Kara Sarrel, Mark Robson, Noah Kauff, Anna Marie Mulligan, Gord Glendon, Hilmi Ozcelik, Bent Ejlertsen, Finn C Nielsen, Lars Jønson, Mette K Andersen, Yuan Chun Ding, Linda Steele, Lenka Foretova, Alex Teulé, Conxi Lazaro, Joan Brunet, Miquel Àngel Pujana, Phuong L Mai, Jennifer T Loud, Christine Walsh, Jenny Lester, Sandra Orsulic, Steven A Narod, Josef Herzog, Sharon R Sand, Silvia Tognazzo, Simona Agata, Tibor Vaszkó, Joellen Weaver, Alexandra V Stavropoulou, Saundra S Buys, Atocha Romero, Miguel de la Hoya, Kristiina Aittomäki, Taru A Muranen, Mercedes Durán, Wendy K Chung, Adriana Lasa, Cecilia M Dorfling, Alexander Miron, Javier Benitez, Leigha Senter, Dezheng Huo, Salina B Chan, Anna P Sokolenko, Jocelyne Chiquette, Laima Tihomirova, Tara M Friebel, Bjarni A Agnarsson, Karen H Lu, Flavio Lejbkowicz, Paul A James, Per Hall, Alison M Dunning, Daniel Tessier, Julie Cunningham, Susan L Slager, Chen Wang, Steven Hart, Kristen Stevens, Jacques Simard, Tomi Pastinen, Vernon S Pankratz, Kenneth Offit, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou.
PLoS Genet.
PUBLISHED: 03-27-2013
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BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
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Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.
Mia M Gaudet, Karoline B Kuchenbaecker, Joseph Vijai, Robert J Klein, Tomas Kirchhoff, Lesley McGuffog, Daniel Barrowdale, Alison M Dunning, Andrew Lee, Joe Dennis, Sue Healey, Ed Dicks, Penny Soucy, Olga M Sinilnikova, Vernon S Pankratz, Xianshu Wang, Ronald C Eldridge, Daniel C Tessier, Daniel Vincent, Francois Bacot, Frans B L Hogervorst, Susan Peock, Dominique Stoppa-Lyonnet, , Paolo Peterlongo, Rita K Schmutzler, Katherine L Nathanson, Marion Piedmonte, Christian F Singer, Mads Thomassen, Thomas V O Hansen, Susan L Neuhausen, Ignacio Blanco, Mark H Greene, Judith Garber, Jeffrey N Weitzel, Irene L Andrulis, David E Goldgar, Emma D'Andrea, Trinidad Caldés, Heli Nevanlinna, Ana Osorio, Elizabeth J van Rensburg, Adalgeir Arason, Gad Rennert, Ans M W van den Ouweland, Annemarie H Van der Hout, Carolien M Kets, Cora M Aalfs, Juul T Wijnen, Margreet G E M Ausems, Debra Frost, Steve Ellis, Elena Fineberg, Radka Platte, D Gareth Evans, Chris Jacobs, Julian Adlard, Marc Tischkowitz, Mary E Porteous, Francesca Damiola, Lisa Golmard, Laure Barjhoux, Michel Longy, Muriel Belotti, Sandra Fert Ferrer, Sylvie Mazoyer, Amanda B Spurdle, Siranoush Manoukian, Monica Barile, Maurizio Genuardi, Norbert Arnold, Alfons Meindl, Christian Sutter, Barbara Wappenschmidt, Susan M Domchek, Georg Pfeiler, Eitan Friedman, Uffe Birk Jensen, Mark Robson, Sohela Shah, Conxi Lazaro, Phuong L Mai, Javier Benitez, Melissa C Southey, Marjanka K Schmidt, Peter A Fasching, Julian Peto, Manjeet K Humphreys, Qin Wang, Kyriaki Michailidou, Elinor J Sawyer, Barbara Burwinkel, Pascal Guénel, Stig E Bojesen, Roger L Milne, Hermann Brenner, Magdalena Lochmann, Kristiina Aittomäki, Thilo Dörk, Sara Margolin, Arto Mannermaa, Diether Lambrechts, Jenny Chang-Claude, Paolo Radice, Graham G Giles, Christopher A Haiman, Robert Winqvist, Peter Devillee, Montserrat Garcia-Closas, Nils Schoof, Maartje J Hooning, Angela Cox, Paul D P Pharoah, Anna Jakubowska, Nick Orr, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Per Hall, Fergus J Couch, Jacques Simard, David Altshuler, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou, Kenneth Offit.
PLoS Genet.
PUBLISHED: 03-27-2013
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Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR?=?0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
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Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.
Stig E Bojesen, Karen A Pooley, Sharon E Johnatty, Jonathan Beesley, Kyriaki Michailidou, Jonathan P Tyrer, Stacey L Edwards, Hilda A Pickett, Howard C Shen, Chanel E Smart, Kristine M Hillman, Phuong L Mai, Kate Lawrenson, Michael D Stutz, Yi Lu, Rod Karevan, Nicholas Woods, Rebecca L Johnston, Juliet D French, Xiaoqing Chen, Maren Weischer, Sune F Nielsen, Melanie J Maranian, Maya Ghoussaini, Shahana Ahmed, Caroline Baynes, Manjeet K Bolla, Qin Wang, Joe Dennis, Lesley McGuffog, Daniel Barrowdale, Andrew Lee, Sue Healey, Michael Lush, Daniel C Tessier, Daniel Vincent, Françis Bacot, , Ignace Vergote, Sandrina Lambrechts, Evelyn Despierre, Harvey A Risch, Anna González-Neira, Mary Anne Rossing, Guillermo Pita, Jennifer A Doherty, Nuria Alvarez, Melissa C Larson, Brooke L Fridley, Nils Schoof, Jenny Chang-Claude, Mine S Cicek, Julian Peto, Kimberly R Kalli, Annegien Broeks, Sebastian M Armasu, Marjanka K Schmidt, Linde M Braaf, Boris Winterhoff, Heli Nevanlinna, Gottfried E Konecny, Diether Lambrechts, Lisa Rogmann, Pascal Guénel, Attila Teoman, Roger L Milne, Joaquín J García, Angela Cox, Vijayalakshmi Shridhar, Barbara Burwinkel, Frederik Marme, Rebecca Hein, Elinor J Sawyer, Christopher A Haiman, Shan Wang-Gohrke, Irene L Andrulis, Kirsten B Moysich, John L Hopper, Kunle Odunsi, Annika Lindblom, Graham G Giles, Hermann Brenner, Jacques Simard, Galina Lurie, Peter A Fasching, Michael E Carney, Paolo Radice, Lynne R Wilkens, Anthony Swerdlow, Marc T Goodman, Hiltrud Brauch, Montserrat Garcia-Closas, Peter Hillemanns, Robert Winqvist, Matthias Dürst, Peter Devilee, Ingo Runnebaum, Anna Jakubowska, Jan Lubiński, Arto Mannermaa, Ralf Bützow, Natalia V Bogdanova, Thilo Dörk, Liisa M Pelttari, Wei Zheng, Arto Leminen, Hoda Anton-Culver, Clareann H Bunker, Vessela Kristensen, Roberta B Ness, Kenneth Muir, Robert Edwards, Alfons Meindl, Florian Heitz, Keitaro Matsuo, Andreas du Bois, Anna H Wu, Philipp Harter, Soo-Hwang Teo, Ira Schwaab, Xiao-Ou Shu, William Blot, Satoyo Hosono, Daehee Kang, Toru Nakanishi, Mikael Hartman, Yasushi Yatabe, Ute Hamann, Beth Y Karlan, Suleeporn Sangrajrang, Susanne Krüger Kjaer, Valerie Gaborieau, Allan Jensen, Diana Eccles, Estrid Høgdall, Chen-Yang Shen, Judith Brown, Yin Ling Woo, Mitul Shah, Mat Adenan Noor Azmi, Robert Luben, Siti Zawiah Omar, Kamila Czene, Robert A Vierkant, Børge G Nordestgaard, Henrik Flyger, Celine Vachon, Janet E Olson, Xianshu Wang, Douglas A Levine, Anja Rudolph, Rachel Palmieri Weber, Dieter Flesch-Janys, Edwin Iversen, Stefan Nickels, Joellen M Schildkraut, Isabel dos Santos Silva, Daniel W Cramer, Lorna Gibson, Kathryn L Terry, Olivia Fletcher, Allison F Vitonis, C Ellen van der Schoot, Elizabeth M Poole, Frans B L Hogervorst, Shelley S Tworoger, Jianjun Liu, Elisa V Bandera, Jingmei Li, Sara H Olson, Keith Humphreys, Irene Orlow, Carl Blomqvist, Lorna Rodriguez-Rodriguez, Kristiina Aittomäki, Helga B Salvesen, Taru A Muranen, Elisabeth Wik, Barbara Brouwers, Camilla Krakstad, Els Wauters, Mari K Halle, Hans Wildiers, Lambertus A Kiemeney, Claire Mulot, Katja K Aben, Pierre Laurent-Puig, Anne Mvan Altena, Thérèse Truong, Leon F A G Massuger, Javier Benitez, Tanja Pejovic, Jose Ignacio Arias Perez, Maureen Hoatlin, M Pilar Zamora, Linda S Cook, Sabapathy P Balasubramanian, Linda E Kelemen, Andreas Schneeweiss, Nhu D Le, Christof Sohn, Angela Brooks-Wilson, Ian Tomlinson, Michael J Kerin, Nicola Miller, Cezary Cybulski, Brian E Henderson, Janusz Menkiszak, Fredrick Schumacher, Nicolas Wentzensen, Loic Le Marchand, Hannah P Yang, Anna Marie Mulligan, Gord Glendon, Svend Aage Engelholm, Julia A Knight, Claus K Høgdall, Carmel Apicella, Martin Gore, Helen Tsimiklis, Honglin Song, Melissa C Southey, Agnes Jager, Ans M Wvan den Ouweland, Robert Brown, John W M Martens, James M Flanagan, Mieke Kriege, James Paul, Sara Margolin, Nadeem Siddiqui, Gianluca Severi, Alice S Whittemore, Laura Baglietto, Valerie McGuire, Christa Stegmaier, Weiva Sieh, Heiko Muller, Volker Arndt, France Labrèche, Yu-Tang Gao, Mark S Goldberg, Gong Yang, Martine Dumont, John R McLaughlin, Arndt Hartmann, Arif B Ekici, Matthias W Beckmann, Catherine M Phelan, Michael P Lux, Jenny Permuth-Wey, Bernard Peissel, Thomas A Sellers, Filomena Ficarazzi, Monica Barile, Argyrios Ziogas, Alan Ashworth, Aleksandra Gentry-Maharaj, Michael Jones, Susan J Ramus, Nick Orr, Usha Menon, Celeste L Pearce, Thomas Brüning, Malcolm C Pike, Yon-Dschun Ko, Jolanta Lissowska, Jonine Figueroa, Jolanta Kupryjanczyk, Stephen J Chanock, Agnieszka Dansonka-Mieszkowska, Arja Jukkola-Vuorinen, Iwona K Rzepecka, Katri Pylkäs, Mariusz Bidzinski, Saila Kauppila, Antoinette Hollestelle, Caroline Seynaeve, Rob A E M Tollenaar, Katarzyna Durda, Katarzyna Jaworska, Jaana M Hartikainen, Veli-Matti Kosma, Vesa Kataja, Natalia N Antonenkova, Jirong Long, Martha Shrubsole, Sandra Deming-Halverson, Artitaya Lophatananon, Pornthep Siriwanarangsan, Sarah Stewart-Brown, Nina Ditsch, Peter Lichtner, Rita K Schmutzler, Hidemi Ito, Hiroji Iwata, Kazuo Tajima, Chiu-Chen Tseng, Daniel O Stram, David Van Den Berg, Cheng Har Yip, M Kamran Ikram, Yew-Ching Teh, Hui Cai, Wei Lu, Lisa B Signorello, Qiuyin Cai, Dong-Young Noh, Keun-Young Yoo, Hui Miao, Philip Tsau-Choong Iau, Yik Ying Teo, James McKay, Charles Shapiro, Foluso Ademuyiwa, George Fountzilas, Chia-Ni Hsiung, Jyh-Cherng Yu, Ming-Feng Hou, Catherine S Healey, Craig Luccarini, Susan Peock, Dominique Stoppa-Lyonnet, Paolo Peterlongo, Timothy R Rebbeck, Marion Piedmonte, Christian F Singer, Eitan Friedman, Mads Thomassen, Kenneth Offit, Thomas V O Hansen, Susan L Neuhausen, Csilla I Szabo, Ignacio Blanco, Judy Garber, Steven A Narod, Jeffrey N Weitzel, Marco Montagna, Edith Olah, Andrew K Godwin, Drakoulis Yannoukakos, David E Goldgar, Trinidad Caldés, Evgeny N Imyanitov, Laima Tihomirova, Banu K Arun, Ian Campbell, Arjen R Mensenkamp, Christi J van Asperen, Kees E P van Roozendaal, Hanne Meijers-Heijboer, J Margriet Collée, Jan C Oosterwijk, Maartje J Hooning, Matti A Rookus, Rob B van der Luijt, Theo A Mvan Os, D Gareth Evans, Debra Frost, Elena Fineberg, Julian Barwell, Lisa Walker, M John Kennedy, Radka Platte, Rosemarie Davidson, Steve D Ellis, Trevor Cole, Brigitte Bressac-de Paillerets, Bruno Buecher, Francesca Damiola, Laurence Faivre, Marc Frénay, Olga M Sinilnikova, Olivier Caron, Sophie Giraud, Sylvie Mazoyer, Valérie Bonadona, Virginie Caux-Moncoutier, Aleksandra Toloczko-Grabarek, Jacek Gronwald, Tomasz Byrski, Amanda B Spurdle, Bernardo Bonanni, Daniela Zaffaroni, Giuseppe Giannini, Loris Bernard, Riccardo Dolcetti, Siranoush Manoukian, Norbert Arnold, Christoph Engel, Helmut Deissler, Kerstin Rhiem, Dieter Niederacher, Hansjoerg Plendl, Christian Sutter, Barbara Wappenschmidt, Ake Borg, Beatrice Melin, Johanna Rantala, Maria Soller, Katherine L Nathanson, Susan M Domchek, Gustavo C Rodriguez, Ritu Salani, Daphne Gschwantler Kaulich, Muy-Kheng Tea, Shani Shimon Paluch, Yael Laitman, Anne-Bine Skytte, Torben A Kruse, Uffe Birk Jensen, Mark Robson, Anne-Marie Gerdes, Bent Ejlertsen, Lenka Foretova, Sharon A Savage, Jenny Lester, Penny Soucy, Karoline B Kuchenbaecker, Curtis Olswold, Julie M Cunningham, Susan Slager, Vernon S Pankratz, Ed Dicks, Sunil R Lakhani, Fergus J Couch, Per Hall, Alvaro N A Monteiro, Simon A Gayther, Paul D P Pharoah, Roger R Reddel, Ellen L Goode, Mark H Greene, Douglas F Easton, Andrew Berchuck, Antonis C Antoniou, Georgia Chenevix-Trench, Alison M Dunning.
Nat. Genet.
PUBLISHED: 01-31-2013
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TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ?480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
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Large-scale genotyping identifies 41 new loci associated with breast cancer risk.
Kyriaki Michailidou, Per Hall, Anna González-Neira, Maya Ghoussaini, Joe Dennis, Roger L Milne, Marjanka K Schmidt, Jenny Chang-Claude, Stig E Bojesen, Manjeet K Bolla, Qin Wang, Ed Dicks, Andrew Lee, Clare Turnbull, Nazneen Rahman, , Olivia Fletcher, Julian Peto, Lorna Gibson, Isabel Dos Santos Silva, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Kamila Czene, Astrid Irwanto, Jianjun Liu, Quinten Waisfisz, Hanne Meijers-Heijboer, Muriel Adank, Rob B van der Luijt, Rebecca Hein, Norbert Dahmen, Lars Beckman, Alfons Meindl, Rita K Schmutzler, Bertram Müller-Myhsok, Peter Lichtner, John L Hopper, Melissa C Southey, Enes Makalic, Daniel F Schmidt, André G Uitterlinden, Albert Hofman, David J Hunter, Stephen J Chanock, Daniel Vincent, Francois Bacot, Daniel C Tessier, Sander Canisius, Lodewyk F A Wessels, Christopher A Haiman, Mitul Shah, Robert Luben, Judith Brown, Craig Luccarini, Nils Schoof, Keith Humphreys, Jingmei Li, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Fergus J Couch, Xianshu Wang, Celine Vachon, Kristen N Stevens, Diether Lambrechts, Matthieu Moisse, Robert Paridaens, Marie-Rose Christiaens, Anja Rudolph, Stefan Nickels, Dieter Flesch-Janys, Nichola Johnson, Zoe Aitken, Kirsimari Aaltonen, Tuomas Heikkinen, Annegien Broeks, Laura J Van't Veer, C Ellen van der Schoot, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Florence Menegaux, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, M Pilar Zamora, Jose Ignacio Arias Perez, Guillermo Pita, M Rosario Alonso, Angela Cox, Ian W Brock, Simon S Cross, Malcolm W R Reed, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Annika Lindblom, Sara Margolin, Maartje J Hooning, Antoinette Hollestelle, Ans M W van den Ouweland, Agnes Jager, Quang M Bui, Jennifer Stone, Gillian S Dite, Carmel Apicella, Helen Tsimiklis, Graham G Giles, Gianluca Severi, Laura Baglietto, Peter A Fasching, Lothar Haeberle, Arif B Ekici, Matthias W Beckmann, Hermann Brenner, Heiko Muller, Volker Arndt, Christa Stegmaier, Anthony Swerdlow, Alan Ashworth, Nick Orr, Michael Jones, Jonine Figueroa, Jolanta Lissowska, Louise Brinton, Mark S Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Hiltrud Brauch, Ute Hamann, Thomas Brüning, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Bernardo Bonanni, Peter Devilee, Rob A E M Tollenaar, Caroline Seynaeve, Christi J van Asperen, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska, Katarzyna Durda, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Natalia V Bogdanova, Natalia N Antonenkova, Thilo Dörk, Vessela N Kristensen, Hoda Anton-Culver, Susan Slager, Amanda E Toland, Stephen Edge, Florentia Fostira, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Aiko Sueta, Anna H Wu, Chiu-Chen Tseng, David Van Den Berg, Daniel O Stram, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Hui Cai, Soo Hwang Teo, Cheng Har Yip, Sze Yee Phuah, Belinda K Cornes, Mikael Hartman, Hui Miao, Wei Yen Lim, Jen-Hwei Sng, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Chen-Yang Shen, Chia-Ni Hsiung, Pei-Ei Wu, Shian-Ling Ding, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, William J Blot, Lisa B Signorello, Qiuyin Cai, Wei Zheng, Sandra Deming-Halverson, Martha Shrubsole, Jirong Long, Jacques Simard, Montse Garcia-Closas, Paul D P Pharoah, Georgia Chenevix-Trench, Alison M Dunning, Javier Benitez, Douglas F Easton.
Nat. Genet.
PUBLISHED: 01-30-2013
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Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ?9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
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Genome-wide association studies identify four ER negative-specific breast cancer risk loci.
Montserrat Garcia-Closas, Fergus J Couch, Sara Lindstrom, Kyriaki Michailidou, Marjanka K Schmidt, Mark N Brook, Nick Orr, Suhn Kyong Rhie, Elio Riboli, Heather S Feigelson, Loic Le Marchand, Julie E Buring, Diana Eccles, Penelope Miron, Peter A Fasching, Hiltrud Brauch, Jenny Chang-Claude, Jane Carpenter, Andrew K Godwin, Heli Nevanlinna, Graham G Giles, Angela Cox, John L Hopper, Manjeet K Bolla, Qin Wang, Joe Dennis, Ed Dicks, Will J Howat, Nils Schoof, Stig E Bojesen, Diether Lambrechts, Annegien Broeks, Irene L Andrulis, Pascal Guénel, Barbara Burwinkel, Elinor J Sawyer, Antoinette Hollestelle, Olivia Fletcher, Robert Winqvist, Hermann Brenner, Arto Mannermaa, Ute Hamann, Alfons Meindl, Annika Lindblom, Wei Zheng, Peter Devillee, Mark S Goldberg, Jan Lubiński, Vessela Kristensen, Anthony Swerdlow, Hoda Anton-Culver, Thilo Dörk, Kenneth Muir, Keitaro Matsuo, Anna H Wu, Paolo Radice, Soo Hwang Teo, Xiao-Ou Shu, William Blot, Daehee Kang, Mikael Hartman, Suleeporn Sangrajrang, Chen-Yang Shen, Melissa C Southey, Daniel J Park, Fleur Hammet, Jennifer Stone, Laura J Van't Veer, Emiel J Rutgers, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Julian Peto, Michael G Schrauder, Arif B Ekici, Matthias W Beckmann, Isabel Dos Santos Silva, Nichola Johnson, Helen Warren, Ian Tomlinson, Michael J Kerin, Nicola Miller, Federick Marme, Andreas Schneeweiss, Christof Sohn, Thérèse Truong, Pierre Laurent-Puig, Pierre Kerbrat, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Roger L Milne, Jose Ignacio Arias Perez, Primitiva Menéndez, Heiko Muller, Volker Arndt, Christa Stegmaier, Peter Lichtner, Magdalena Lochmann, Christina Justenhoven, Yon-Dschun Ko, , Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Dario Greco, Tuomas Heikkinen, Hidemi Ito, Hiroji Iwata, Yasushi Yatabe, Natalia N Antonenkova, Sara Margolin, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Rosemary Balleine, Chiu-Chen Tseng, David Van Den Berg, Daniel O Stram, Patrick Neven, Anne-Sophie Dieudonné, Karin Leunen, Anja Rudolph, Stefan Nickels, Dieter Flesch-Janys, Paolo Peterlongo, Bernard Peissel, Loris Bernard, Janet E Olson, Xianshu Wang, Kristen Stevens, Gianluca Severi, Laura Baglietto, Catriona McLean, Gerhard A Coetzee, Ye Feng, Brian E Henderson, Fredrick Schumacher, Natalia V Bogdanova, France Labrèche, Martine Dumont, Cheng Har Yip, Nur Aishah Mohd Taib, Ching-Yu Cheng, Martha Shrubsole, Jirong Long, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Robertus A E M Tollenaar, Caroline M Seynaeve, Mieke Kriege, Maartje J Hooning, Ans M W van den Ouweland, Carolien H M van Deurzen, Wei Lu, Yu-Tang Gao, Hui Cai, Sabapathy P Balasubramanian, Simon S Cross, Malcolm W R Reed, Lisa Signorello, Qiuyin Cai, Mitul Shah, Hui Miao, Ching Wan Chan, Kee Seng Chia, Anna Jakubowska, Katarzyna Jaworska, Katarzyna Durda, Chia-Ni Hsiung, Pei-Ei Wu, Jyh-Cherng Yu, Alan Ashworth, Michael Jones, Daniel C Tessier, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Daniel Vincent, Francois Bacot, Christine B Ambrosone, Elisa V Bandera, Esther M John, Gary K Chen, Jennifer J Hu, Jorge L Rodriguez-Gil, Leslie Bernstein, Michael F Press, Regina G Ziegler, Robert M Millikan, Sandra L Deming-Halverson, Sarah Nyante, Sue A Ingles, Quinten Waisfisz, Helen Tsimiklis, Enes Makalic, Daniel Schmidt, Minh Bui, Lorna Gibson, Bertram Müller-Myhsok, Rita K Schmutzler, Rebecca Hein, Norbert Dahmen, Lars Beckmann, Kirsimari Aaltonen, Kamila Czene, Astrid Irwanto, Jianjun Liu, Clare Turnbull, Nazneen Rahman, Hanne Meijers-Heijboer, André G Uitterlinden, Fernando Rivadeneira, Curtis Olswold, Susan Slager, Robert Pilarski, Foluso Ademuyiwa, Irene Konstantopoulou, Nicholas G Martin, Grant W Montgomery, Dennis J Slamon, Claudia Rauh, Michael P Lux, Sebastian M Jud, Thomas Brüning, Joellen Weaver, Priyanka Sharma, Harsh Pathak, Will Tapper, Sue Gerty, Lorraine Durcan, Dimitrios Trichopoulos, Rosario Tumino, Petra H Peeters, Rudolf Kaaks, Daniele Campa, Federico Canzian, Elisabete Weiderpass, Mattias Johansson, Kay-Tee Khaw, Ruth Travis, Francoise Clavel-Chapelon, Laurence N Kolonel, Constance Chen, Andy Beck, Susan E Hankinson, Christine D Berg, Robert N Hoover, Jolanta Lissowska, Jonine D Figueroa, Daniel I Chasman, Mia M Gaudet, W Ryan Diver, Walter C Willett, David J Hunter, Jacques Simard, Javier Benitez, Alison M Dunning, Mark E Sherman, Georgia Chenevix-Trench, Stephen J Chanock, Per Hall, Paul D P Pharoah, Celine Vachon, Douglas F Easton, Christopher A Haiman, Peter Kraft.
Nat. Genet.
PUBLISHED: 01-29-2013
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Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
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Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers.
Juliet D French, Maya Ghoussaini, Stacey L Edwards, Kerstin B Meyer, Kyriaki Michailidou, Shahana Ahmed, Sofia Khan, Mel J Maranian, Martin O'Reilly, Kristine M Hillman, Joshua A Betts, Thomas Carroll, Peter J Bailey, Ed Dicks, Jonathan Beesley, Jonathan Tyrer, Ana-Teresa Maia, Andrew Beck, Nicholas W Knoblauch, Constance Chen, Peter Kraft, Daniel Barnes, Anna González-Neira, M Rosario Alonso, Daniel Herrero, Daniel C Tessier, Daniel Vincent, Francois Bacot, Craig Luccarini, Caroline Baynes, Don Conroy, Joe Dennis, Manjeet K Bolla, Qin Wang, John L Hopper, Melissa C Southey, Marjanka K Schmidt, Annegien Broeks, Senno Verhoef, Sten Cornelissen, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Peter A Fasching, Christian R Loehberg, Arif B Ekici, Matthias W Beckmann, Julian Peto, Isabel Dos Santos Silva, Nichola Johnson, Zoe Aitken, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Florence Menegaux, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Roger L Milne, M Pilar Zamora, José Ignacio Arias Perez, Javier Benitez, Hoda Anton-Culver, Hermann Brenner, Heiko Muller, Volker Arndt, Christa Stegmaier, Alfons Meindl, Peter Lichtner, Rita K Schmutzler, Christoph Engel, Hiltrud Brauch, Ute Hamann, Christina Justenhoven, , Kirsimari Aaltonen, Päivi Heikkilä, Kristiina Aittomäki, Carl Blomqvist, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Aiko Sueta, Natalia V Bogdanova, Natalia N Antonenkova, Thilo Dörk, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Anna H Wu, Chiu-Chen Tseng, David Van Den Berg, Daniel O Stram, Diether Lambrechts, Stéphanie Peeters, Ann Smeets, Giuseppe Floris, Jenny Chang-Claude, Anja Rudolph, Stefan Nickels, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Domenico Sardella, Fergus J Couch, Xianshu Wang, Vernon S Pankratz, Adam Lee, Graham G Giles, Gianluca Severi, Laura Baglietto, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Soo Hwang Teo, Cheng Har Yip, Char-Hong Ng, Eranga Nishanthie Vithana, Vessela Kristensen, Wei Zheng, Sandra Deming-Halverson, Martha Shrubsole, Jirong Long, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Peter Devilee, Caroline Seynaeve, Montserrat Garcia-Closas, Jonine Figueroa, Stephen J Chanock, Jolanta Lissowska, Kamila Czene, Daniel Klevebring, Nils Schoof, Maartje J Hooning, John W M Martens, J Margriet Collée, Madeleine Tilanus-Linthorst, Per Hall, Jingmei Li, Jianjun Liu, Keith Humphreys, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Hui Cai, Angela Cox, Sabapathy P Balasubramanian, William Blot, Lisa B Signorello, Qiuyin Cai, Paul D P Pharoah, Catherine S Healey, Mitul Shah, Karen A Pooley, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Mikael Hartman, Hui Miao, Jen-Hwei Sng, Xueling Sim, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Suleeporn Sangrajrang, Valerie Gaborieau, James McKay, Amanda E Toland, Christine B Ambrosone, Drakoulis Yannoukakos, Andrew K Godwin, Chen-Yang Shen, Chia-Ni Hsiung, Pei-Ei Wu, Shou-Tung Chen, Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk J Schoemaker, Bruce A J Ponder, Heli Nevanlinna, Melissa A Brown, Georgia Chenevix-Trench, Douglas F Easton, Alison M Dunning.
Am. J. Hum. Genet.
PUBLISHED: 01-03-2013
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Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.
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Downregulation of serine protease HTRA1 is associated with poor survival in breast cancer.
PLoS ONE
PUBLISHED: 01-01-2013
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HTRA1 is a highly conserved serine protease which has been implicated in suppression of epithelial-to-mesenchymal-transition (EMT) and cell motility in breast cancer. Its prognostic relevance for breast cancer is unclear so far. Therefore, we evaluated the impact of HTRA1 mRNA expression on patient outcome using a cohort of 131 breast cancer patients as well as a validation cohort including 2809 publically available data sets. Additionally, we aimed at investigating for the presence of promoter hypermethylation as a mechanism for silencing the HTRA1 gene in breast tumors. HTRA1 downregulation was detected in more than 50% of the breast cancer specimens and was associated with higher tumor stage (p?=?0.025). By applying Cox proportional hazard models, we observed favorable overall (OS) and disease-free survival (DFS) related to high HTRA1 expression (HR?=?0.45 [CI 0.23-0.90], p?=?0.023; HR?=?0.55 [CI 0.32-0.94], p?=?0.028, respectively), with even more pronounced impact in node-positive patients (HR?=?0.21 [CI 0.07-0.63], p?=?0.006; HR?=?0.29 [CI 0.13-0.65], p?=?0.002, respectively). Moreover, HTRA1 remained a statistically significant factor predicting DFS among established clinical parameters in the multivariable analysis. Its impact on patient outcome was independently confirmed in the validation set (for relapse-free survival (n?=?2809): HR?=?0.79 [CI 0.7-0.9], log-rank p?=?0.0003; for OS (n?=?971): HR?=?0.63 [CI 0.48-0.83], log-rank p?=?0.0009). In promoter analyses, we in fact detected methylation of HTRA1 in a small subset of breast cancer specimens (two out of a series of 12), and in MCF-7 breast cancer cells which exhibited 22-fold lower HTRA1 mRNA expression levels compared to unmethylated MDA-MB-231 cells. In conclusion, we show that downregulation of HTRA1 is associated with shorter patient survival, particularly in node-positive breast cancer. Since HTRA1 loss was demonstrated to induce EMT and cancer cell invasion, these patients might benefit from demethylating agents or histone deacetylase inhibitors previously reported to lead to HTRA1 upregulation, or from novel small-molecule inhibitors targeting EMT-related processes.
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Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).
Nasim Mavaddat, Daniel Barrowdale, Irene L Andrulis, Susan M Domchek, Diana Eccles, Heli Nevanlinna, Susan J Ramus, Amanda Spurdle, Mark Robson, Mark Sherman, Anna Marie Mulligan, Fergus J Couch, Christoph Engel, Lesley McGuffog, Sue Healey, Olga M Sinilnikova, Melissa C Southey, Mary Beth Terry, David Goldgar, Frances O'Malley, Esther M John, Ramunas Janavicius, Laima Tihomirova, Thomas V O Hansen, Finn C Nielsen, Ana Osorio, Alexandra Stavropoulou, Javier Benitez, Siranoush Manoukian, Bernard Peissel, Monica Barile, Sara Volorio, Barbara Pasini, Riccardo Dolcetti, Anna Laura Putignano, Laura Ottini, Paolo Radice, Ute Hamann, Muhammad U Rashid, Frans B Hogervorst, Mieke Kriege, Rob B van der Luijt, , Susan Peock, Debra Frost, D Gareth Evans, Carole Brewer, Lisa Walker, Mark T Rogers, Lucy E Side, Catherine Houghton, Joellen Weaver, Andrew K Godwin, Rita K Schmutzler, Barbara Wappenschmidt, Alfons Meindl, Karin Kast, Norbert Arnold, Dieter Niederacher, Christian Sutter, Helmut Deissler, Doroteha Gadzicki, Sabine Preisler-Adams, Raymonda Varon-Mateeva, Ines Schönbuchner, Heidrun Gevensleben, Dominique Stoppa-Lyonnet, Muriel Belotti, Laure Barjhoux, Claudine Isaacs, Beth N Peshkin, Trinidad Caldés, Miguel de la Hoya, Carmen Cañadas, Tuomas Heikkinen, Päivi Heikkilä, Kristiina Aittomäki, Ignacio Blanco, Conxi Lazaro, Joan Brunet, Bjarni A Agnarsson, Adalgeir Arason, Rosa B Barkardottir, Martine Dumont, Jacques Simard, Marco Montagna, Simona Agata, Emma D'Andrea, Max Yan, Stephen Fox, Timothy R Rebbeck, Wendy Rubinstein, Nadine Tung, Judy E Garber, Xianshu Wang, Zachary Fredericksen, Vernon S Pankratz, Noralane M Lindor, Csilla Szabó, Kenneth Offit, Rita Sakr, Mia M Gaudet, Christian F Singer, Muy-Kheng Tea, Christine Rappaport, Phuong L Mai, Mark H Greene, Anna Sokolenko, Evgeny Imyanitov, Amanda Ewart Toland, Leigha Senter, Kevin Sweet, Mads Thomassen, Anne-Marie Gerdes, Torben Kruse, Maria Caligo, Paolo Aretini, Johanna Rantala, Anna von Wachenfeld, Karin Henriksson, Linda Steele, Susan L Neuhausen, Robert Nussbaum, Mary Beattie, Kunle Odunsi, Lara Sucheston, Simon A Gayther, Kate Nathanson, Jenny Gross, Christine Walsh, Beth Karlan, Georgia Chenevix-Trench, Douglas F Easton, Antonis C Antoniou.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 12-05-2011
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Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.
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7q21-rs6964587 and breast cancer risk: an extended case-control study by the Breast Cancer Association Consortium.
J. Med. Genet.
PUBLISHED: 09-21-2011
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Using the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authors have now assessed this association more comprehensively using 16 independent case-control studies.
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Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers.
David G Cox, Jacques Simard, Daniel Sinnett, Yosr Hamdi, Penny Soucy, Manon Ouimet, Laure Barjhoux, Carole Verny-Pierre, Lesley McGuffog, Sue Healey, Csilla Szabó, Mark H Greene, Phuong L Mai, Irene L Andrulis, , Mads Thomassen, Anne-Marie Gerdes, Maria A Caligo, Eitan Friedman, Yael Laitman, Bella Kaufman, Shani S Paluch, Ake Borg, Per Karlsson, Marie Stenmark Askmalm, Gisela Barbany Bustinza, Katherine L Nathanson, Susan M Domchek, Timothy R Rebbeck, Javier Benitez, Ute Hamann, Matti A Rookus, Ans M W van den Ouweland, Margreet G E M Ausems, Cora M Aalfs, Christi J van Asperen, Peter Devilee, Hans J J P Gille, Susan Peock, Debra Frost, D Gareth Evans, Ros Eeles, Louise Izatt, Julian Adlard, Joan Paterson, Jacqueline Eason, Andrew K Godwin, Marie-Alice Remon, Virginie Moncoutier, Marion Gauthier-Villars, Christine Lasset, Sophie Giraud, Agnès Hardouin, Pascaline Berthet, Hagay Sobol, François Eisinger, Brigitte Bressac de Paillerets, Olivier Caron, Capucine Delnatte, David Goldgar, Alex Miron, Hilmi Ozcelik, Saundra Buys, Melissa C Southey, Mary Beth Terry, Christian F Singer, Anne-Catharina Dressler, Muy-Kheng Tea, Thomas V O Hansen, Oskar Johannsson, Marion Piedmonte, Gustavo C Rodriguez, Jack B Basil, Stephanie Blank, Amanda E Toland, Marco Montagna, Claudine Isaacs, Ignacio Blanco, Simon A Gayther, Kirsten B Moysich, Rita K Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Dieter Niederacher, Christian Sutter, Dorothea Gadzicki, Britta Fiebig, Trinidad Caldés, Rachel Laframboise, Heli Nevanlinna, Xiaoqing Chen, Jonathan Beesley, Amanda B Spurdle, Susan L Neuhausen, Yuan C Ding, Fergus J Couch, Xianshu Wang, Paolo Peterlongo, Siranoush Manoukian, Loris Bernard, Paolo Radice, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Olga M Sinilnikova.
Hum. Mol. Genet.
PUBLISHED: 09-02-2011
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Mutations in the BRCA1 gene substantially increase a womans lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.
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Confirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer.
Roger L Milne, Ellen L Goode, Montserrat Garcia-Closas, Fergus J Couch, Gianluca Severi, Rebecca Hein, Zachary Fredericksen, Nuria Malats, M Pilar Zamora, José Ignacio Arias Perez, Javier Benitez, Thilo Dörk, Peter Schürmann, Johann H Karstens, Peter Hillemanns, Angela Cox, Ian W Brock, Graeme Elliot, Simon S Cross, Sheila Seal, Clare Turnbull, Anthony Renwick, Nazneen Rahman, Chen-Yang Shen, Jyh-Cherng Yu, Chiun-Sheng Huang, Ming-Feng Hou, Børge G Nordestgaard, Stig E Bojesen, Charlotte Lanng, Grethe Grenaker Alnæs, Vessela Kristensen, Anne-Lise Børrensen-Dale, John L Hopper, Gillian S Dite, Carmel Apicella, Melissa C Southey, Diether Lambrechts, Betul T Yesilyurt, Giuseppe Floris, Karin Leunen, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Jenny Chang-Claude, Shan Wang-Gohrke, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Graham G Giles, Laura Baglietto, Esther M John, Alexander Miron, Stephen J Chanock, Jolanta Lissowska, Mark E Sherman, Jonine D Figueroa, Natalia V Bogdanova, Natalia N Antonenkova, Iosif V Zalutsky, Yuri I Rogov, Peter A Fasching, Christian M Bayer, Arif B Ekici, Matthias W Beckmann, Hermann Brenner, Heiko Muller, Volker Arndt, Christa Stegmaier, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Alfons Meindl, Joerg Heil, Claus R Bartram, Rita K Schmutzler, Gilles D Thomas, Robert N Hoover, Olivia Fletcher, Lorna J Gibson, Isabel Dos Santos Silva, Julian Peto, Stefan Nickels, Dieter Flesch-Janys, Hoda Anton-Culver, Argyrios Ziogas, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Nicola Miller, Marjanka K Schmidt, Annegien Broeks, Laura J van 't Veer, Rob A E M Tollenaar, Paul D P Pharoah, Alison M Dunning, Karen A Pooley, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska, Katarzyna Durda, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Sei-Hyun Ahn, David J Hunter, Susan E Hankinson, Peter Kraft, Sara Lindstrom, Xiaoqing Chen, Jonathan Beesley, Ute Hamann, Volker Harth, Christina Justenhoven, , Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Maartje Hooning, Antoinette Hollestelle, Rogier A Oldenburg, Madeleine Tilanus-Linthorst, Elza Khusnutdinova, Marina Bermisheva, Darya Prokofieva, Albina Farahtdinova, Janet E Olson, Xianshu Wang, Manjeet K Humphreys, Qin Wang, Georgia Chenevix-Trench, Douglas F Easton.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 07-27-2011
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The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium.
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Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.
Christopher A Maxwell, Javier Benitez, Laia Gómez-Baldó, Ana Osorio, Núria Bonifaci, Ricardo Fernandez-Ramires, Sylvain V Costes, Elisabet Guinó, Helen Chen, Gareth J R Evans, Pooja Mohan, Isabel Català, Anna Petit, Helena Aguilar, Alberto Villanueva, Alvaro Aytes, Jordi Serra-Musach, Gad Rennert, Flavio Lejbkowicz, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Carla B Ripamonti, Bernardo Bonanni, Alessandra Viel, Anna Allavena, Loris Bernard, Paolo Radice, Eitan Friedman, Bella Kaufman, Yael Laitman, Maya Dubrovsky, Roni Milgrom, Anna Jakubowska, Cezary Cybulski, Bohdan Górski, Katarzyna Jaworska, Katarzyna Durda, Grzegorz Sukiennicki, Jan Lubiński, Yin Yao Shugart, Susan M Domchek, Richard Letrero, Barbara L Weber, Frans B L Hogervorst, Matti A Rookus, J Margriet Collée, Peter Devilee, Marjolijn J Ligtenberg, Rob B van der Luijt, Cora M Aalfs, Quinten Waisfisz, Juul Wijnen, Cornelis E P van Roozendaal, , Douglas F Easton, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Patricia Harrington, D Gareth Evans, Fiona Lalloo, Rosalind Eeles, Louise Izatt, Carol Chu, Diana Eccles, Fiona Douglas, Carole Brewer, Heli Nevanlinna, Tuomas Heikkinen, Fergus J Couch, Noralane M Lindor, Xianshu Wang, Andrew K Godwin, Maria A Caligo, Grazia Lombardi, Niklas Loman, Per Karlsson, Hans Ehrencrona, Anna von Wachenfeldt, Rosa Bjork Barkardottir, Ute Hamann, Muhammad U Rashid, Adriana Lasa, Trinidad Caldés, Raquel Andrés, Michael Schmitt, Volker Assmann, Kristen Stevens, Kenneth Offit, João Curado, Hagen Tilgner, Roderic Guigo, Gemma Aiza, Joan Brunet, Joan Castellsagué, Griselda Martrat, Ander Urruticoechea, Ignacio Blanco, Laima Tihomirova, David E Goldgar, Saundra Buys, Esther M John, Alexander Miron, Melissa Southey, Mary B Daly, Rita K Schmutzler, Barbara Wappenschmidt, Alfons Meindl, Norbert Arnold, Helmut Deissler, Raymonda Varon-Mateeva, Christian Sutter, Dieter Niederacher, Evgeny Imyamitov, Olga M Sinilnikova, Dominique Stoppa-Lyonne, Sylvie Mazoyer, Carole Verny-Pierre, Laurent Castera, Antoine de Pauw, Yves-Jean Bignon, Nancy Uhrhammer, Jean-Philippe Peyrat, Philippe Vennin, Sandra Fert Ferrer, Marie-Agnès Collonge-Rame, Isabelle Mortemousque, Amanda B Spurdle, Jonathan Beesley, Xiaoqing Chen, Sue Healey, Mary Helen Barcellos-Hoff, Marc Vidal, Stephen B Gruber, Conxi Lazaro, Gabriel Capellà, Lesley McGuffog, Katherine L Nathanson, Antonis C Antoniou, Georgia Chenevix-Trench, Markus C Fleisch, Victor Moreno, Miguel Angel Pujana.
PLoS Biol.
PUBLISHED: 06-08-2011
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Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n?=?7,584, weighted hazard ratio ((w)HR)?=?1.09 (95% CI 1.02-1.16), p(trend)?=?0.017; and n?=?3,965, (w)HR?=?1.04 (95% CI 0.94-1.16), p(trend)?=?0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.
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Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers.
Antonis C Antoniou, Christiana Kartsonaki, Olga M Sinilnikova, Penny Soucy, Lesley McGuffog, Sue Healey, Andrew Lee, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Elisa Cattaneo, Monica Barile, Valeria Pensotti, Barbara Pasini, Riccardo Dolcetti, Giuseppe Giannini, Anna Laura Putignano, Liliana Varesco, Paolo Radice, Phuong L Mai, Mark H Greene, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, Mads Thomassen, Anne-Marie Gerdes, Torben A Kruse, Uffe Birk Jensen, Dorthe G Crüger, Maria A Caligo, Yael Laitman, Roni Milgrom, Bella Kaufman, Shani Paluch-Shimon, Eitan Friedman, Niklas Loman, Katja Harbst, Annika Lindblom, Brita Arver, Hans Ehrencrona, Beatrice Melin, , Katherine L Nathanson, Susan M Domchek, Timothy Rebbeck, Ania Jakubowska, Jan Lubiński, Jacek Gronwald, Tomasz Huzarski, Tomasz Byrski, Cezary Cybulski, Bohdan Górski, Ana Osorio, Teresa Ramón Y Cajal, Florentia Fostira, Raquel Andrés, Javier Benitez, Ute Hamann, Frans B Hogervorst, Matti A Rookus, Maartje J Hooning, Marcel R Nelen, Rob B van der Luijt, Theo A M van Os, Christi J van Asperen, Peter Devilee, Hanne E J Meijers-Heijboer, Encarna B Gomez Garcia, Susan Peock, Margaret Cook, Debra Frost, Radka Platte, Jean Leyland, D Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Julian Adlard, Rosemarie Davidson, Diana Eccles, Kai-Ren Ong, Jackie Cook, Fiona Douglas, Joan Paterson, M John Kennedy, Zosia Miedzybrodzka, Andrew Godwin, Dominique Stoppa-Lyonnet, Bruno Buecher, Muriel Belotti, Carole Tirapo, Sylvie Mazoyer, Laure Barjhoux, Christine Lasset, Dominique Leroux, Laurence Faivre, Myriam Bronner, Fabienne Prieur, Catherine Noguès, Etienne Rouleau, Pascal Pujol, Isabelle Coupier, Marc Frénay, John L Hopper, Mary B Daly, Mary B Terry, Esther M John, Saundra S Buys, Yosuf Yassin, Alexander Miron, David Goldgar, Christian F Singer, Muy-Kheng Tea, Georg Pfeiler, Anne Catharina Dressler, Thomas V O Hansen, Lars Jønson, Bent Ejlertsen, Rosa Bjork Barkardottir, Tomas Kirchhoff, Kenneth Offit, Marion Piedmonte, Gustavo Rodriguez, Laurie Small, John Boggess, Stephanie Blank, Jack Basil, Masoud Azodi, Amanda Ewart Toland, Marco Montagna, Silvia Tognazzo, Simona Agata, Evgeny Imyanitov, Ramunas Janavicius, Conxi Lazaro, Ignacio Blanco, Paul D P Pharoah, Lara Sucheston, Beth Y Karlan, Christine S Walsh, Edith Olah, Aniko Bozsik, Soo-Hwang Teo, Joyce L Seldon, Mary S Beattie, Elizabeth J van Rensburg, Michelle D Sluiter, Orland Díez, Rita K Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Ina Ruehl, Raymonda Varon-Mateeva, Karin Kast, Helmut Deissler, Dieter Niederacher, Norbert Arnold, Dorothea Gadzicki, Ines Schönbuchner, Trinidad Caldés, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittomäki, Martine Dumont, Jocelyne Chiquette, Marc Tischkowitz, Xiaoqing Chen, Jonathan Beesley, Amanda B Spurdle, Susan L Neuhausen, Yuan Chun Ding, Zachary Fredericksen, Xianshu Wang, Vernon S Pankratz, Fergus Couch, Jacques Simard, Douglas F Easton, Georgia Chenevix-Trench.
Hum. Mol. Genet.
PUBLISHED: 05-18-2011
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Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.
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Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.
Anna Marie Mulligan, Fergus J Couch, Daniel Barrowdale, Susan M Domchek, Diana Eccles, Heli Nevanlinna, Susan J Ramus, Mark Robson, Mark Sherman, Amanda B Spurdle, Barbara Wappenschmidt, Andrew Lee, Lesley McGuffog, Sue Healey, Olga M Sinilnikova, Ramunas Janavicius, Thomas Vo Hansen, Finn C Nielsen, Bent Ejlertsen, Ana Osorio, Iván Muñoz-Repeto, Mercedes Durán, Javier Godino, Maroulio Pertesi, Javier Benitez, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Elisa Cattaneo, Bernardo Bonanni, Alessandra Viel, Barbara Pasini, Laura Papi, Laura Ottini, Antonella Savarese, Loris Bernard, Paolo Radice, Ute Hamann, Martijn Verheus, Hanne E J Meijers-Heijboer, Juul Wijnen, Encarna B Gomez Garcia, Marcel R Nelen, C Marleen Kets, Caroline Seynaeve, Madeleine M A Tilanus-Linthorst, Rob B van der Luijt, Theo van Os, Matti Rookus, Debra Frost, J Louise Jones, D Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Julian Adlard, Rosemarie Davidson, Jackie Cook, Alan Donaldson, Huw Dorkins, Helen Gregory, Jacqueline Eason, Catherine Houghton, Julian Barwell, Lucy E Side, Emma McCann, Alex Murray, Susan Peock, Andrew K Godwin, Rita K Schmutzler, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Ina Ruehl, Norbert Arnold, Dieter Niederacher, Christian Sutter, Helmut Deissler, Dorothea Gadzicki, Karin Kast, Sabine Preisler-Adams, Raymonda Varon-Mateeva, Ines Schoenbuchner, Britta Fiebig, Wolfram Heinritz, Dieter Schäfer, Heidrun Gevensleben, Virginie Caux-Moncoutier, Marion Fassy-Colcombet, Francois Cornelis, Sylvie Mazoyer, Mélanie Léoné, Nadia Boutry-Kryza, Agnès Hardouin, Pascaline Berthet, Danièle Muller, Jean-Pierre Fricker, Isabelle Mortemousque, Pascal Pujol, Isabelle Coupier, Marine Lebrun, Caroline Kientz, Michel Longy, Nicolas Sévenet, Dominique Stoppa-Lyonnet, Claudine Isaacs, Trinidad Caldés, Miguel de la Hoya, Tuomas Heikkinen, Kristiina Aittomäki, Ignacio Blanco, Conxi Lazaro, Rosa B Barkardottir, Penny Soucy, Martine Dumont, Jacques Simard, Marco Montagna, Silvia Tognazzo, Emma D'Andrea, Stephen Fox, Max Yan, Tim Rebbeck, Olufunmilayo Olopade, Jeffrey N Weitzel, Henry T Lynch, Patricia A Ganz, Gail E Tomlinson, Xianshu Wang, Zachary Fredericksen, Vernon S Pankratz, Noralane M Lindor, Csilla Szabó, Kenneth Offit, Rita Sakr, Mia Gaudet, Jasmine Bhatia, Noah Kauff, Christian F Singer, Muy-Kheng Tea, Daphne Gschwantler-Kaulich, Anneliese Fink-Retter, Phuong L Mai, Mark H Greene, Evgeny Imyanitov, Frances P O'Malley, Hilmi Ozcelik, Gordon Glendon, Amanda E Toland, Anne-Marie Gerdes, Mads Thomassen, Torben A Kruse, Uffe Birk Jensen, Anne-Bine Skytte, Maria A Caligo, Maria Soller, Karin Henriksson, von Anna Wachenfeldt, Brita Arver, Marie Stenmark-Askmalm, Per Karlsson, Yuan Chun Ding, Susan L Neuhausen, Mary Beattie, Paul D P Pharoah, Kirsten B Moysich, Katherine L Nathanson, Beth Y Karlan, Jenny Gross, Esther M John, Mary B Daly, Saundra M Buys, Melissa C Southey, John L Hopper, Mary Beth Terry, Wendy Chung, Alexander F Miron, David Goldgar, Georgia Chenevix-Trench, Douglas F Easton, Irene L Andrulis, Antonis C Antoniou, .
Breast Cancer Res.
PUBLISHED: 04-27-2011
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Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.
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Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers.
Kate M Im, Tomas Kirchhoff, Xianshu Wang, Todd Green, Clement Y Chow, Joseph Vijai, Joshua Korn, Mia M Gaudet, Zachary Fredericksen, V Shane Pankratz, Candace Guiducci, Andrew Crenshaw, Lesley McGuffog, Christiana Kartsonaki, Jonathan Morrison, Sue Healey, Olga M Sinilnikova, Phuong L Mai, Mark H Greene, Marion Piedmonte, Wendy S Rubinstein, , Frans B Hogervorst, Matti A Rookus, J Margriet Collée, Nicoline Hoogerbrugge, Christi J van Asperen, Hanne E J Meijers-Heijboer, Cees E Van Roozendaal, Trinidad Caldés, Pedro Pérez-Segura, Anna Jakubowska, Jan Lubiński, Tomasz Huzarski, Paweł Blecharz, Heli Nevanlinna, Kristiina Aittomäki, Conxi Lazaro, Ignacio Blanco, Rosa B Barkardottir, Marco Montagna, Emma D'Andrea, Peter Devilee, Olufunmilayo I Olopade, Susan L Neuhausen, Bernard Peissel, Bernardo Bonanni, Paolo Peterlongo, Christian F Singer, Gad Rennert, Flavio Lejbkowicz, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, Amanda Ewart Toland, Maria Adelaide Caligo, Mary S Beattie, Salina Chan, Susan M Domchek, Katherine L Nathanson, Timothy R Rebbeck, Catherine Phelan, Steven Narod, Esther M John, John L Hopper, Saundra S Buys, Mary B Daly, Melissa C Southey, Mary-Beth Terry, Nadine Tung, Thomas V O Hansen, Ana Osorio, Javier Benitez, Mercedes Durán, Jeffrey N Weitzel, Judy Garber, Ute Hamann, Susan Peock, Margaret Cook, Clare T Oliver, Debra Frost, Radka Platte, D Gareth Evans, Ros Eeles, Louise Izatt, Joan Paterson, Carole Brewer, Shirley Hodgson, Patrick J Morrison, Mary Porteous, Lisa Walker, Mark T Rogers, Lucy E Side, Andrew K Godwin, Rita K Schmutzler, Barbara Wappenschmidt, Yael Laitman, Alfons Meindl, Helmut Deissler, Raymonda Varon-Mateeva, Sabine Preisler-Adams, Karin Kast, Laurence Venat-Bouvet, Dominique Stoppa-Lyonnet, Georgia Chenevix-Trench, Douglas F Easton, Robert J Klein, Mark J Daly, Eitan Friedman, Michael Dean, Andrew G Clark, David M Altshuler, Antonis C Antoniou, Fergus J Couch, Kenneth Offit, Bert Gold.
Hum. Genet.
PUBLISHED: 04-20-2011
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Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.
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Full-length L1CAM and not its ?2?27 splice variant promotes metastasis through induction of gelatinase expression.
PLoS ONE
PUBLISHED: 03-24-2011
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Tumour-specific splicing is known to contribute to cancer progression. In the case of the L1 cell adhesion molecule (L1CAM), which is expressed in many human tumours and often linked to bad prognosis, alternative splicing results in a full-length form (FL-L1CAM) and a splice variant lacking exons 2 and 27 (SV-L1CAM). It has not been elucidated so far whether SV-L1CAM, classically considered as tumour-associated, or whether FL-L1CAM is the metastasis-promoting isoform. Here, we show that both variants were expressed in human ovarian carcinoma and that exposure of tumour cells to pro-metastatic factors led to an exclusive increase of FL-L1CAM expression. Selective overexpression of one isoform in different tumour cells revealed that only FL-L1CAM promoted experimental lung and/or liver metastasis in mice. In addition, metastasis formation upon up-regulation of FL-L1CAM correlated with increased invasive potential and elevated Matrix metalloproteinase (MMP)-2 and -9 expression and activity in vitro as well as enhanced gelatinolytic activity in vivo. In conclusion, we identified FL-L1CAM as the metastasis-promoting isoform, thereby exemplifying that high expression of a so-called tumour-associated variant, here SV-L1CAM, is not per se equivalent to a decisive role of this isoform in tumour progression.
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Hereditary breast and ovarian cancer: new genes, new treatments, new concepts.
Dtsch Arztebl Int
PUBLISHED: 03-14-2011
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Every year, 60,000 women in Germany are found to have breast cancer, and 9000 to have ovarian cancer. Familial clustering of carcinoma is seen in about 20% of cases.
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Association of death receptor 4 variant (683A > C) with ovarian cancer risk in BRCA1 mutation carriers.
Int. J. Cancer
PUBLISHED: 02-23-2011
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Dysregulation of apoptosis plays an important role in carcinogenesis. Therefore, apoptosis-associated genes like the death receptor 4 (DR4, TRAIL-R1) are interesting candidates for modifying the penetrance of breast and ovarian cancer in carriers of BRCA1 and BRCA2 mutations. The DR-4 haplotype 626C-683C [626C > G, Thr209Arg (rs4871857) and 683A > C, Glu228Ala (rs17088993)] has recently been linked to an increased risk of breast cancer. To evaluate whether DR4 626C > G or DR4 683A > C modifies the risk of breast or ovarian cancer in carriers of BRCA1 and BRCA2 mutations, we undertook a national multicenter study including data of 840 carriers of breast cancer gene (BRCA) mutations. DNA samples were collected from 12 German research centers between 1996 and 2005 and were genotyped by the Taqman allelic discrimination assay. The association between genotypes and incidence of breast or ovarian cancer data was evaluated using a Cox proportional hazards regression model. We found evidence for a significant association of DR4 683A > C with a higher risk for ovarian cancer in carriers of BRCA1 mutations [n = 557, hazard ratio 1.78 (1.24-2.55), p = 0.009]. Our results thus indicate that the DR4 683A > C variant modifies the risk of ovarian cancer in carriers of BRCA1 mutations.
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Germline mutations in the PALB2 gene are population specific and occur with low frequencies in familial breast cancer.
Hum. Mutat.
PUBLISHED: 02-01-2011
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The Partner and Localizer of BRCA2 (PALB2) protein has been linked to Fanconi anemia and breast cancer predisposition. Here we present data of a comprehensive mutation screening of the PALB2 gene in 818 familial cases of breast cancer from Germany. By analyzing the entire coding region of PALB2, we found seven truncating mutations (six of them novel) in families tested negative for BRCA1/2-mutations. In addition, two novel potentially disease causing missense mutations were found. Remarkably, only one mutation reported previously in other populations, was also identified in the German population. No PALB2 mutation carriers were identified in 450 unaffected controls. Thus, our observations indicate a low prevalence of deleterious PALB2 mutations and a specific mutation profile within the German population. As PALB2-deficient tumors were shown to be sensitive to Poly(ADP-ribose) Polymerase (PARP) inhibitors, our study has implications for newly developed, favorable treatment options in familial breast cancer.
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Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers.
Susan J Ramus, Christiana Kartsonaki, Simon A Gayther, Paul D P Pharoah, Olga M Sinilnikova, Jonathan Beesley, Xiaoqing Chen, Lesley McGuffog, Sue Healey, Fergus J Couch, Xianshu Wang, Zachary Fredericksen, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Gaia Roversi, Monica Barile, Alessandra Viel, Anna Allavena, Laura Ottini, Laura Papi, Viviana Gismondi, Fabio Capra, Paolo Radice, Mark H Greene, Phuong L Mai, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, , Mads Thomassen, Anne-Marie Gerdes, Torben A Kruse, Dorthe Crüger, Uffe Birk Jensen, Maria Adelaide Caligo, Hakan Olsson, Ulf Kristoffersson, Annika Lindblom, Brita Arver, Per Karlsson, Marie Stenmark Askmalm, Ake Borg, Susan L Neuhausen, Yuan Chun Ding, Katherine L Nathanson, Susan M Domchek, Anna Jakubowska, Jan Lubiński, Tomasz Huzarski, Tomasz Byrski, Jacek Gronwald, Bohdan Górski, Cezary Cybulski, Tadeusz Dębniak, Ana Osorio, Mercedes Durán, Maria-Isabel Tejada, Javier Benitez, Ute Hamann, Matti A Rookus, Senno Verhoef, Madeleine A Tilanus-Linthorst, Maaike P Vreeswijk, Danielle Bodmer, Margreet G E M Ausems, Theo A van Os, Christi J Asperen, Marinus J Blok, Hanne E J Meijers-Heijboer, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Alison M Dunning, D Gareth Evans, Ros Eeles, Gabriella Pichert, Trevor Cole, Shirley Hodgson, Carole Brewer, Patrick J Morrison, Mary Porteous, M John Kennedy, Mark T Rogers, Lucy E Side, Alan Donaldson, Helen Gregory, Andrew Godwin, Dominique Stoppa-Lyonnet, Virginie Moncoutier, Laurent Castera, Sylvie Mazoyer, Laure Barjhoux, Valérie Bonadona, Dominique Leroux, Laurence Faivre, Rosette Lidereau, Catherine Noguès, Yves-Jean Bignon, Fabienne Prieur, Marie-Agnès Collonge-Rame, Laurence Venat-Bouvet, Sandra Fert-Ferrer, Alex Miron, Saundra S Buys, John L Hopper, Mary B Daly, Esther M John, Mary Beth Terry, David Goldgar, Thomas V O Hansen, Lars Jønson, Bent Ejlertsen, Bjarni A Agnarsson, Kenneth Offit, Tomas Kirchhoff, Joseph Vijai, Ana V C Dutra-Clarke, Jennifer A Przybylo, Marco Montagna, Cinzia Casella, Evgeny N Imyanitov, Ramunas Janavicius, Ignacio Blanco, Conxi Lazaro, Kirsten B Moysich, Beth Y Karlan, Jenny Gross, Mary S Beattie, Rita Schmutzler, Barbara Wappenschmidt, Alfons Meindl, Ina Ruehl, Britta Fiebig, Christian Sutter, Norbert Arnold, Helmut Deissler, Raymonda Varon-Mateeva, Karin Kast, Dieter Niederacher, Dorothea Gadzicki, Trinidad Caldés, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittomäki, Jacques Simard, Penny Soucy, Amanda B Spurdle, Helene Holland, Georgia Chenevix-Trench, Douglas F Easton, Antonis C Antoniou.
J. Natl. Cancer Inst.
PUBLISHED: 12-17-2010
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Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2.
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Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction.
Antonis C Antoniou, Jonathan Beesley, Lesley McGuffog, Olga M Sinilnikova, Sue Healey, Susan L Neuhausen, Yuan Chun Ding, Timothy R Rebbeck, Jeffrey N Weitzel, Henry T Lynch, Claudine Isaacs, Patricia A Ganz, Gail Tomlinson, Olufunmilayo I Olopade, Fergus J Couch, Xianshu Wang, Noralane M Lindor, Vernon S Pankratz, Paolo Radice, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Monica Barile, Alessandra Viel, Anna Allavena, Valentina Dall'Olio, Paolo Peterlongo, Csilla I Szabo, Michal Zikán, Kathleen Claes, Bruce Poppe, Lenka Foretova, Phuong L Mai, Mark H Greene, Gad Rennert, Flavio Lejbkowicz, Gord Glendon, Hilmi Ozcelik, Irene L Andrulis, , Mads Thomassen, Anne-Marie Gerdes, Lone Sunde, Dorthe Crüger, Uffe Birk Jensen, Maria Caligo, Eitan Friedman, Bella Kaufman, Yael Laitman, Roni Milgrom, Maya Dubrovsky, Shimrit Cohen, Ake Borg, Helena Jernström, Annika Lindblom, Johanna Rantala, Marie Stenmark-Askmalm, Beatrice Melin, Kate Nathanson, Susan Domchek, Ania Jakubowska, Jan Lubiński, Tomasz Huzarski, Ana Osorio, Adriana Lasa, Mercedes Durán, Maria-Isabel Tejada, Javier Godino, Javier Benitez, Ute Hamann, Mieke Kriege, Nicoline Hoogerbrugge, Rob B van der Luijt, Christi J van Asperen, Peter Devilee, E J Meijers-Heijboer, Marinus J Blok, Cora M Aalfs, Frans Hogervorst, Matti Rookus, Margaret Cook, Clare Oliver, Debra Frost, Don Conroy, D Gareth Evans, Fiona Lalloo, Gabriella Pichert, Rosemarie Davidson, Trevor Cole, Jackie Cook, Joan Paterson, Shirley Hodgson, Patrick J Morrison, Mary E Porteous, Lisa Walker, M John Kennedy, Huw Dorkins, Susan Peock, Andrew K Godwin, Dominique Stoppa-Lyonnet, Antoine de Pauw, Sylvie Mazoyer, Valérie Bonadona, Christine Lasset, Hélène Dreyfus, Dominique Leroux, Agnès Hardouin, Pascaline Berthet, Laurence Faivre, Catherine Loustalot, Tetsuro Noguchi, Hagay Sobol, Etienne Rouleau, Catherine Noguès, Marc Frénay, Laurence Venat-Bouvet, John L Hopper, Mary B Daly, Mary B Terry, Esther M John, Saundra S Buys, Yosuf Yassin, Alexander Miron, David Goldgar, Christian F Singer, Anne Catharina Dressler, Daphne Gschwantler-Kaulich, Georg Pfeiler, Thomas V O Hansen, Lars Jønson, Bjarni A Agnarsson, Tomas Kirchhoff, Kenneth Offit, Vincent Devlin, Ana Dutra-Clarke, Marion Piedmonte, Gustavo C Rodriguez, Katie Wakeley, John F Boggess, Jack Basil, Peter E Schwartz, Stephanie V Blank, Amanda Ewart Toland, Marco Montagna, Cinzia Casella, Evgeny Imyanitov, Laima Tihomirova, Ignacio Blanco, Conxi Lazaro, Susan J Ramus, Lara Sucheston, Beth Y Karlan, Jenny Gross, Rita Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Magdalena Lochmann, Norbert Arnold, Simone Heidemann, Raymonda Varon-Mateeva, Dieter Niederacher, Christian Sutter, Helmut Deissler, Dorothea Gadzicki, Sabine Preisler-Adams, Karin Kast, Ines Schönbuchner, Trinidad Caldés, Miguel de la Hoya, Kristiina Aittomäki, Heli Nevanlinna, Jacques Simard, Amanda B Spurdle, Helene Holland, Xiaoqing Chen, Radka Platte, Georgia Chenevix-Trench, Douglas F Easton.
Cancer Res.
PUBLISHED: 11-30-2010
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The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.
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Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 10-26-2010
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The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population.
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Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls.
Olivia Fletcher, Nichola Johnson, Isabel Dos Santos Silva, Nick Orr, Alan Ashworth, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, Barbara Burwinkel, Claus R Bartram, Alfons Meindl, Rita K Schmutzler, Angela Cox, Ian Brock, Graeme Elliott, Malcolm W R Reed, Melissa C Southey, Letitia Smith, Amanda B Spurdle, John L Hopper, Fergus J Couch, Janet E Olson, Xianshu Wang, Zachary Fredericksen, Peter Schürmann, Regina Waltes, Michael Bremer, Thilo Dörk, Peter Devilee, Christie J van Asperen, Rob A E M Tollenaar, Caroline Seynaeve, Per Hall, Kamila Czene, Keith Humphreys, Jianjun Liu, Shahana Ahmed, Alison M Dunning, Melanie Maranian, Paul D P Pharoah, Georgia Chenevix-Trench, , Jonathan Beesley, Natalia V Bogdanova, Natalia N Antonenkova, Iosif V Zalutsky, Hoda Anton-Culver, Argyrios Ziogas, Hiltrud Brauch, Yon-Dschun Ko, Ute Hamann, Peter A Fasching, Reiner Strick, Arif B Ekici, Matthias W Beckmann, Graham G Giles, Gianluca Severi, Laura Baglietto, Dallas R English, Roger L Milne, Javier Benitez, José Ignacio Arias, Guillermo Pita, Børge G Nordestgaard, Stig E Bojesen, Henrik Flyger, Daehee Kang, Keun-Young Yoo, Dong Young Noh, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Montserrat Garcia-Closas, Stephen Chanock, Jolanta Lissowska, Louise A Brinton, Jenny Chang-Claude, Shan Wang-Gohrke, Annegien Broeks, Marjanka K Schmidt, Flora E van Leeuwen, Laura J Van't Veer, Sara Margolin, Annika Lindblom, Manjeet K Humphreys, Jonathan Morrison, Radka Platte, Douglas F Easton, Julian Peto.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 09-10-2010
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Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious.
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Genetic variants within miR-126 and miR-335 are not associated with breast cancer risk.
Breast Cancer Res. Treat.
PUBLISHED: 08-30-2010
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MicroRNAs (miRNAs) are 20-22 nt non-coding RNAs which promote the degradation of target mRNAs or repression of the translation of mRNAs by sequence specific targeting. Many miRNAs are considered as oncogenes or tumor suppressors. MiR-126 and miR-335 play roles in the suppression of breast cancer metastasis by inhibiting tumor growth, proliferation, and cell invasion. The effects of SNPs within the two miRNAs are still unknown. In our study, we analyzed two SNPs, rs4636297 within miR-126 and rs41272366 within miR-335, in three study populations for a putative association with breast cancer risk. We compared the genotype and allele frequencies of rs4636297 and rs41272366 in 2854 cases versus 3188 controls of the three study populations independently and combined. None of the performed analyses showed statistically significant results. In conclusion, our data suggest that the two genetic variants within miR-126 and miR-335 are not associated with breast cancer risk.
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Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers.
Breast Cancer Res.
PUBLISHED: 08-27-2010
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Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies.
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Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers.
Hum. Mol. Genet.
PUBLISHED: 04-23-2010
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Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 x 10(-3)) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (P(trend) < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR = 0.78, 95% CI: 0.69-0.90, P(trend) = 3.6 x 10(-4) and HR = 1.25, 95% CI: 1.10-1.41, P(trend) = 4.2 x 10(-4)), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR = 1.55, 95% CI: 1.25-1.92, P(trend) = 6 x 10(-5) and HR = 1.37, 95% CI: 1.16-1.62, P(trend) = 1.7 x 10(-4)). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.
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A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population.
Antonis C Antoniou, Xianshu Wang, Zachary S Fredericksen, Lesley McGuffog, Robert Tarrell, Olga M Sinilnikova, Sue Healey, Jonathan Morrison, Christiana Kartsonaki, Timothy Lesnick, Maya Ghoussaini, Daniel Barrowdale, , Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Diana Eccles, D Gareth Evans, Ros Eeles, Louise Izatt, Carol Chu, Fiona Douglas, Joan Paterson, Dominique Stoppa-Lyonnet, Claude Houdayer, Sylvie Mazoyer, Sophie Giraud, Christine Lasset, Audrey Remenieras, Olivier Caron, Agnès Hardouin, Pascaline Berthet, Frans B L Hogervorst, Matti A Rookus, Agnes Jager, Ans van den Ouweland, Nicoline Hoogerbrugge, Rob B van der Luijt, Hanne Meijers-Heijboer, Encarna B Gomez Garcia, Peter Devilee, Maaike P G Vreeswijk, Jan Lubiński, Anna Jakubowska, Jacek Gronwald, Tomasz Huzarski, Tomasz Byrski, Bohdan Górski, Cezary Cybulski, Amanda B Spurdle, Helene Holland, David E Goldgar, Esther M John, John L Hopper, Melissa Southey, Saundra S Buys, Mary B Daly, Mary-Beth Terry, Rita K Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Sabine Preisler-Adams, Norbert Arnold, Dieter Niederacher, Christian Sutter, Susan M Domchek, Katherine L Nathanson, Timothy Rebbeck, Joanne L Blum, Marion Piedmonte, Gustavo C Rodriguez, Katie Wakeley, John F Boggess, Jack Basil, Stephanie V Blank, Eitan Friedman, Bella Kaufman, Yael Laitman, Roni Milgrom, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, Tomas Kirchhoff, Joseph Vijai, Mia M Gaudet, David Altshuler, Candace Guiducci, Niklas Loman, Katja Harbst, Johanna Rantala, Hans Ehrencrona, Anne-Marie Gerdes, Mads Thomassen, Lone Sunde, Paolo Peterlongo, Siranoush Manoukian, Bernardo Bonanni, Alessandra Viel, Paolo Radice, Trinidad Caldés, Miguel de la Hoya, Christian F Singer, Anneliese Fink-Retter, Mark H Greene, Phuong L Mai, Jennifer T Loud, Lucia Guidugli, Noralane M Lindor, Thomas V O Hansen, Finn C Nielsen, Ignacio Blanco, Conxi Lazaro, Judy Garber, Susan J Ramus, Simon A Gayther, Catherine Phelan, Stephen Narod, Csilla I Szabo, Javier Benitez, Ana Osorio, Heli Nevanlinna, Tuomas Heikkinen, Maria A Caligo, Mary S Beattie, Ute Hamann, Andrew K Godwin, Marco Montagna, Cinzia Casella, Susan L Neuhausen, Beth Y Karlan, Nadine Tung, Amanda E Toland, Jeffrey Weitzel, Olofunmilayo Olopade, Jacques Simard, Penny Soucy, Wendy S Rubinstein, Adalgeir Arason, Gad Rennert, Nicholas G Martin, Grant W Montgomery, Jenny Chang-Claude, Dieter Flesch-Janys, Hiltrud Brauch, Gianluca Severi, Laura Baglietto, Angela Cox, Simon S Cross, Penelope Miron, Sue M Gerty, William Tapper, Drakoulis Yannoukakos, George Fountzilas, Peter A Fasching, Matthias W Beckmann, Isabel Dos Santos Silva, Julian Peto, Diether Lambrechts, Robert Paridaens, Thomas Rüdiger, Asta Försti, Robert Winqvist, Katri Pylkäs, Robert B Diasio, Adam M Lee, Jeanette Eckel-Passow, Celine Vachon, Fiona Blows, Kristy Driver, Alison Dunning, Paul P D Pharoah, Kenneth Offit, V Shane Pankratz, Hakon Hakonarson, Georgia Chenevix-Trench, Douglas F Easton, Fergus J Couch.
Nat. Genet.
PUBLISHED: 03-30-2010
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Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P(trend) = 2.3 × 10?? to P(trend) = 3.9 × 10??), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P(trend) = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P(trend) = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (P(trend) = 1 × 10??) to P(trend) = 8 × 10??; rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P(trend) = 1.1 × 10??
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Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene.
Nat. Genet.
PUBLISHED: 03-22-2010
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Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia-like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the common disease, rare allele hypothesis.
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X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options.
Blood
PUBLISHED: 02-19-2010
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A large proportion of patients with mutations in the Wiskott-Aldrich syndrome (WAS) protein gene exhibit the milder phenotype termed X-linked thrombocytopenia (XLT). Whereas stem cell transplantation at an early age is the treatment of choice for patients with WAS, therapeutic options for patients with XLT are controversial. In a retrospective multicenter study we defined the clinical phenotype of XLT and determined the probability of severe disease-related complications in patients older than 2 years with documented WAS gene mutations and mild-to-moderate eczema or mild, infrequent infections. Enrolled were 173 patients (median age, 11.5 years) from 12 countries spanning 2830 patient-years. Serious bleeding episodes occurred in 13.9%, life-threatening infections in 6.9%, autoimmunity in 12.1%, and malignancy in 5.2% of patients. Overall and event-free survival probabilities were not significantly influenced by the type of mutation or intravenous immunoglobulin or antibiotic prophylaxis. Splenectomy resulted in increased risk of severe infections. This analysis of the clinical outcome and molecular basis of patients with XLT shows excellent long-term survival but also a high probability of severe disease-related complications. These observations will allow better decision making when considering treatment options for individual patients with XLT.
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A variant affecting miRNAs binding in the circadian gene Neuronal PAS domain protein 2 (NPAS2) is not associated with breast cancer risk.
Breast Cancer Res. Treat.
PUBLISHED: 02-12-2010
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Disruption of the circadian rhythm has been reported to increase the risk of breast cancer. A single nucleotide polymorphism (SNP) rs2305160 in Neuronal PAS domain protein 2 (NPAS2), the largest circadian gene, was identified as a breast cancer susceptibility locus. In the current study, we found a novel functional SNP (rs3739008) located at 3UTR of NPAS2 and the C to T changing of the SNP may disrupt the binding of microRNA- (miR-) 17-5p and miR-519e to the 3UTR of NPAS2. We then typed this SNP in case-control studies of both Chinese and Germany populations to test its putative associations with breast cancer risk. However, we failed to find any significant associations by different genetic models (dominant genetic model, adjusted OR = 1.13, 95% CI = 0.95-1.35 for the Chinese population and adjusted OR = 0.99, 95% CI = 0.85-1.16 for the Germany population). Although we did not find significant associations at population levels from both Chinese and Germany case-control studies, due to the functional relevance of rs3739008 on NASP2 expression, it will be promising to investigate the influence of this variant on clinical characteristics of breast cancer and breast cancer survival.
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Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.
Cell
PUBLISHED: 01-16-2010
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We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.
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Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers.
J. Clin. Oncol.
PUBLISHED: 10-26-2009
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To estimate the risk for contralateral breast cancer in members of BRCA1- and BRCA2-positive families and to determine predictive risk factors.
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Breast cancer susceptibility: current knowledge and implications for genetic counselling.
Eur. J. Hum. Genet.
PUBLISHED: 09-02-2009
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Breast cancer is the most common malignancy in women in the Western world. Except for the high breast cancer risk in BRCA1 and BRCA2 mutation carriers as well as the risk for breast cancer in certain rare syndromes caused by mutations in TP53, STK11, PTEN, CDH1, NF1 or NBN, familial clustering of breast cancer remains largely unexplained. Despite significant efforts, BRCA3 could not be identified, but several reports have recently been published on genes involved in DNA repair and single nucleotide polymorphisms (SNPs) associated with an increased breast cancer risk. Although candidate gene approaches demonstrated moderately increased breast cancer risks for rare mutations in genes involved in DNA repair (ATM, CHEK2, BRIP1, PALB2 and RAD50), genome-wide association studies identified several SNPs as low-penetrance breast cancer susceptibility polymorphisms within genes as well as in chromosomal loci with no known genes (FGFR2, TOX3, LSP1, MAP3K1, TGFB1, 2q35 and 8q). Some of these low-penetrance breast cancer susceptibility polymorphisms also act as modifier genes in BRCA1/BRCA2 mutation carriers. This review not only outlines the recent key developments and potential clinical benefit for preventive management and therapy but also discusses the current limitations of genetic testing of variants associated with intermediate and low breast cancer risk.
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Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers.
Antonis C Antoniou, Olga M Sinilnikova, Lesley McGuffog, Sue Healey, Heli Nevanlinna, Tuomas Heikkinen, Jacques Simard, Amanda B Spurdle, Jonathan Beesley, Xiaoqing Chen, , Susan L Neuhausen, Yuan C Ding, Fergus J Couch, Xianshu Wang, Zachary Fredericksen, Paolo Peterlongo, Bernard Peissel, Bernardo Bonanni, Alessandra Viel, Loris Bernard, Paolo Radice, Csilla I Szabo, Lenka Foretova, Michal Zikán, Kathleen Claes, Mark H Greene, Phuong L Mai, Gad Rennert, Flavio Lejbkowicz, Irene L Andrulis, Hilmi Ozcelik, Gord Glendon, Anne-Marie Gerdes, Mads Thomassen, Lone Sunde, Maria A Caligo, Yael Laitman, Tair Kontorovich, Shimrit Cohen, Bella Kaufman, Efrat Dagan, Ruth Gershoni Baruch, Eitan Friedman, Katja Harbst, Gisela Barbany-Bustinza, Johanna Rantala, Hans Ehrencrona, Per Karlsson, Susan M Domchek, Katherine L Nathanson, Ana Osorio, Ignacio Blanco, Adriana Lasa, Javier Benitez, Ute Hamann, Frans B L Hogervorst, Matti A Rookus, J Margriet Collée, Peter Devilee, Marjolijn J Ligtenberg, Rob B van der Luijt, Cora M Aalfs, Quinten Waisfisz, Juul Wijnen, Cornelis E P van Roozendaal, Susan Peock, Margaret Cook, Debra Frost, Clare Oliver, Radka Platte, D Gareth Evans, Fiona Lalloo, Rosalind Eeles, Louise Izatt, Rosemarie Davidson, Carol Chu, Diana Eccles, Trevor Cole, Shirley Hodgson, Andrew K Godwin, Dominique Stoppa-Lyonnet, Bruno Buecher, Mélanie Léoné, Brigitte Bressac-de Paillerets, Audrey Remenieras, Olivier Caron, Gilbert M Lenoir, Nicolas Sévenet, Michel Longy, Sandra Fert Ferrer, Fabienne Prieur, David Goldgar, Alexander Miron, Esther M John, Saundra S Buys, Mary B Daly, John L Hopper, Mary Beth Terry, Yosuf Yassin, Christian Singer, Daphne Gschwantler-Kaulich, Christine Staudigl, Thomas V O Hansen, Rosa Bjork Barkardottir, Tomas Kirchhoff, Prodipto Pal, Kristi Kosarin, Kenneth Offit, Marion Piedmonte, Gustavo C Rodriguez, Katie Wakeley, John F Boggess, Jack Basil, Peter E Schwartz, Stephanie V Blank, Amanda E Toland, Marco Montagna, Cinzia Casella, Evgeny N Imyanitov, Anna Allavena, Rita K Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Dieter Niederacher, Helmut Deissler, Britta Fiebig, Christian Suttner, Ines Schönbuchner, Dorothea Gadzicki, Trinidad Caldés, Miguel de la Hoya, Karen A Pooley, Douglas F Easton, Georgia Chenevix-Trench.
Hum. Mol. Genet.
PUBLISHED: 08-05-2009
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Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.
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Nuclear receptor coregulator SNP discovery and impact on breast cancer risk.
BMC Cancer
PUBLISHED: 07-30-2009
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Coregulator proteins are "master regulators", directing transcriptional and posttranscriptional regulation of many target genes, and are critical in many normal physiological processes, but also in hormone driven diseases, such as breast cancer. Little is known on how genetic changes in these genes impact disease development and progression. Thus, we set out to identify novel single nucleotide polymorphisms (SNPs) within SRC-1 (NCoA1), SRC-3 (NCoA3, AIB1), NCoR (NCoR1), and SMRT (NCoR2), and test the most promising SNPs for associations with breast cancer risk.
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A genetic variant in the pre-miR-27a oncogene is associated with a reduced familial breast cancer risk.
Breast Cancer Res. Treat.
PUBLISHED: 07-30-2009
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MicroRNAs (miRNAs) regulate pathways involved in cell differentiation, proliferation, development, and apoptosis by degradation of target mRNAs and/or repression of their translation. Although the single nucleotide polymorphisms (SNPs) in miRNAs target sites have been studied, the effects of SNPs in miRNAs are largely unknown. In our study, we first systematically sequenced miRNA genes reported to be involved in breast cancer to identify/verify SNPs. We analyzed four SNPs, one located in the pre-miRNA and the other three located in miRNA flanking regions, for a putative association with breast cancer risk. The SNP rs895819, located in the terminal loop of pre-miRNA-27a, showed a protective effect. In a large familial breast cancer study cohort, the rare [G] allele of rs895819 was found to be less frequent in the cases than in the controls, indicating a reduced familial breast cancer risk ([G] vs. [A]: OR = 0.88, 95% CI 0.78-0.99, P = 0.0287). Furthermore, age stratification revealed that the protective effect was mainly observed in the age group < 50 years of age ([G] vs. [A]: OR = 0.83, 95% CI 0.70-0.98, P = 0.0314), whereas no significant effect was observed in the age group >or= 50 years of age, indicating a possible hormone-related effect. It has been shown that artificial mutations in the terminal loop of miR-27a can block the maturation process of the miRNA. We hypothesize that the G-variant of rs895819 might impair the maturation of the oncogenic miR-27a and thus, is associated with familial breast cancer risk.
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Risk of estrogen receptor-positive and -negative breast cancer and single-nucleotide polymorphism 2q35-rs13387042.
Roger L Milne, Javier Benitez, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, José Ignacio Arias, M Pilar Zamora, Barbara Burwinkel, Claus R Bartram, Alfons Meindl, Rita K Schmutzler, Angela Cox, Ian Brock, Graeme Elliott, Malcolm W R Reed, Melissa C Southey, Letitia Smith, Amanda B Spurdle, John L Hopper, Fergus J Couch, Janet E Olson, Xianshu Wang, Zachary Fredericksen, Peter Schürmann, Michael Bremer, Peter Hillemanns, Thilo Dörk, Peter Devilee, Christie J van Asperen, Rob A E M Tollenaar, Caroline Seynaeve, Per Hall, Kamila Czene, Jianjun Liu, Yuqing Li, Shahana Ahmed, Alison M Dunning, Melanie Maranian, Paul D P Pharoah, Georgia Chenevix-Trench, Jonathan Beesley, , Natalia V Bogdanova, Natalia N Antonenkova, Iosif V Zalutsky, Hoda Anton-Culver, Argyrios Ziogas, Hiltrud Brauch, Christina Justenhoven, Yon-Dschun Ko, Susanne Haas, Peter A Fasching, Reiner Strick, Arif B Ekici, Matthias W Beckmann, Graham G Giles, Gianluca Severi, Laura Baglietto, Dallas R English, Olivia Fletcher, Nichola Johnson, Isabel Dos Santos Silva, Julian Peto, Clare Turnbull, Sarah Hines, Anthony Renwick, Nazneen Rahman, Børge G Nordestgaard, Stig E Bojesen, Henrik Flyger, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Montserrat Garcia-Closas, Stephen Chanock, Jolanta Lissowska, Louise A Brinton, Jenny Chang-Claude, Shan Wang-Gohrke, Chen-Yang Shen, Hui-Chun Wang, Jyh-Cherng Yu, Sou-Tong Chen, Marina Bermisheva, Tatjana Nikolaeva, Elza Khusnutdinova, Manjeet K Humphreys, Jonathan Morrison, Radka Platte, Douglas F Easton.
J. Natl. Cancer Inst.
PUBLISHED: 06-30-2009
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A recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)-positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium.
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KIF21A variant R954W in familial or sporadic cases of CFEOM1.
Eur J Ophthalmol
PUBLISHED: 06-25-2009
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To demonstrate the clinical characteristics and determine mutations in the KIF21A gene, encoding a kinesin motor protein in patients with congenital fibrosis of the extraocular muscles (CFEOM) type 1.
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Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation.
J. Clin. Invest.
PUBLISHED: 05-09-2009
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The fatal immune dysregulation that sometimes follows EBV infection in boys has been linked to mutations in two X chromosome-encoded genes, SLAM-associated protein (SAP) and X-linked inhibitor of apoptosis (XIAP). In this study we describe 2 girls from a consanguineous Turkish family who died after developing severe immune dysregulation and therapy-resistant EBV-positive B cell proliferation following EBV infection. SNP array-based genome-wide linkage analysis revealed IL-2-inducible T cell kinase (ITK) as a candidate gene for this immunodeficiency syndrome. Both girls harbored a homozygous missense mutation that led to substitution of a highly conserved residue (R335W) in the SH2 domain of ITK. Characteristics of ITK deficiency in mouse models, such as absence of NKT cells and high levels of eomesodermin in CD8+ cells, were seen in either one or both of the girls. Two lines of evidence suggested that R335W caused instability of the ITK protein. First, in silico modeling of the mutant protein predicted destabilization of the SH2 domain. Additionally, Western blot analysis revealed that, unlike wild-type ITK, the R335W mutant was nearly undetectable when expressed in 293 T cells. Our results suggest that ITK deficiency causes what we believe to be a novel immunodeficiency syndrome that leads to a fatal inadequate immune response to EBV. Because ITK deficiency resembles EBV-associated lymphoproliferative disorders in boys, we suggest that this molecular cause should be considered during diagnosis and treatment.
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Identification of Novel Susceptibility Genes for Breast Cancer - Genome-Wide Association Studies or Evaluation of Candidate Genes?
Breast Care (Basel)
PUBLISHED: 04-24-2009
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To determine the genetic components that constitute polygenic traits in familial or sporadic breast cancer, low-risk variants on the one hand and mutations conferring moderate penetrance on the other hand have to be identified. While members of the latter group were found by comprehensive screening of candidate genes which are, like the 2 highly penetrant genes BRCA1/BRCA2, located in the DNA repair pathway, the development of novel techniques was urgently needed to identify low-risk variants. The hybridization of chips which contain several hundred thousand single nucleotide polymorphisms (SNPs) with several thousand DNAs from either sporadic breast cancer cases or healthy controls (genome-wide association study, GWAS) has already led to the detection of at least 8 low-risk variants, conferring odds ratios of 1.06-1.64. As they are common in the population, it is likely that extended GWAS will develop a genetic pattern that is able to discriminate women suitable or not for population screening programs.
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A breast cancer risk haplotype in the caspase-8 gene.
Cancer Res.
PUBLISHED: 03-24-2009
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Recent large-scale studies have been successful in identifying common, low-penetrance variants associated with common cancers. One such variant in the caspase-8 (CASP8) gene, D302H (rs1045485), has been confirmed to be associated with breast cancer risk, although the functional effect of this polymorphism (if any) is not yet clear. In order to further map the CASP8 gene with respect to breast cancer susceptibility, we performed extensive haplotype analyses using single nucleotide polymorphisms (SNP) chosen to tag all common variations in the gene (tSNP). We used a staged study design based on 3,200 breast cancer and 3,324 control subjects from the United Kingdom, Utah, and Germany. Using a haplotype-mining algorithm in the UK cohort, we identified a four-SNP haplotype that was significantly associated with breast cancer and that was superior to any other single or multi-locus combination (P=8.0 x 10(-5)), with a per allele odds ratio and 95% confidence interval of 1.30 (1.12-1.49). The result remained significant after adjustment for the multiple testing inherent in mining techniques (false discovery rate, q=0.044). As expected, this haplotype includes the D302H locus. Multicenter analyses on a subset of the tSNPs yielded consistent results. This risk haplotype is likely to carry one or more underlying breast cancer susceptibility alleles, making it an excellent candidate for resequencing in homozygous individuals. An understanding of the mode of action of these alleles will aid risk assessment and may lead to the identification of novel treatment targets in breast cancer.
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Identification of brain- and bone-specific breast cancer metastasis genes.
Cancer Lett.
PUBLISHED: 03-21-2009
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In breast cancer, metastases are relatively widely distributed, with the most common sites being bone, regional lymph nodes, lung, liver, and brain. The detailed mechanism of organ-specific metastasis is poorly understood. In this study, we initiated a search for genes that are implicated in brain or bone metastasis of primary human breast cancer. We generated gene expression profiles of 18 brain and eight bone metastases derived from primary breast tumors. We identified 73 genes differentially expressed between brain and bone metastases. Visualization of the differential gene expression profiles by correspondence and cluster analyses shows that the metastases clearly separate into two distinct groups as an exact reflection of their site of metastasis. Moreover, the analysis of this gene set in primary breast tumors relapsing to either bone or brain allowed accurate categorization of the tumors according to their metastatic site. The identified genes may prove to be excellent markers to predict the site of metastasis in breast cancer patients and could lead to tailor-made therapy to an individual patient.
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Decreased expression of angiogenesis antagonist EFEMP1 in sporadic breast cancer is caused by aberrant promoter methylation and points to an impact of EFEMP1 as molecular biomarker.
Int. J. Cancer
PUBLISHED: 03-04-2009
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EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) was recently described as an antagonist of angiogenesis. Motivated by a strong dependence of tumor growth and metastasis on angiogenesis, we investigated the role of EFEMP1 in human breast cancer. We applied RNA microarray expression analysis and quantitative real-time PCR (QRT) in a total of 45 sporadic breast cancer tissues and found EFEMP1 down-regulation in 59% and 61% of the analyzed tissues, respectively. This down-regulation was confirmed on protein level. Immunohistochemistry in 211 breast cancer tissues resulted in reduced or even abolished EFEMP1 expression in 57-62.5% of the tumors. Bisulphite genomic sequencing in breast cancer cell lines and primary breast cancer tissues revealed promoter methylation as the major cause of this down-regulation. Furthermore, analysis of 203 clinically well characterized primary breast cancers displayed a significant correlation of reduced EFEMP1 protein expression with poor disease-free (p = 0.037) and overall survival (p = 0.032), particularly in those node-positive patients who received adjuvant anthracycline-based chemotherapy, but not in those treated by either cyclophosphamide-methotrexate-5-fluorouracil (CMF) or Tamoxifen. In summary, the presented data demonstrate for the first time the reduced EFEMP1 expression on RNA and protein level in a substantial number of sporadic breast carcinomas and its correlation with epigenetic alterations. Furthermore, these data point towards a possible predictive impact of EFEMP1 expression in primary breast cancer.
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A variant affecting a putative miRNA target site in estrogen receptor (ESR) 1 is associated with breast cancer risk in premenopausal women.
Carcinogenesis
PUBLISHED: 02-13-2009
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MicroRNAs (miRNAs) negatively regulate expression of target transcripts by hybridization to complementary sites of their messenger RNA targets. Chen et al. have described several putative functional single nucleotide polymorphisms (SNPs) in miRNA target sites. Here, we selected 11 miRNA target site SNPs located in 3 untranslated regions of genes involved in cancer and breast cancer to analyze their impact on breast cancer risk using a large familial study population. Whereas no association was observed for 10 SNPs, a significant association was revealed for the variant affecting a miRNA target site in the estrogen receptor (ESR) 1. Age stratification showed that the association was stronger in premenopausal women [C versus T: odds ratio (OR) = 0.60, confidence interval (CI) = 0.41-0.89, P = 0.010]. Furthermore, the effect was stronger in high-risk familial cases (C versus T: OR = 0.42, CI = 0.25-0.71, P = 0.0009). Clinical studies have shown that elimination of ESR1 significantly reduces breast cancer risk. Thus, therapies that inhibit ESR1 are used for breast cancer treatment. According to in silico analysis, ESR1_rs2747648 affects the binding capacity of miR-453, which is stronger when the C allele is present. In contrast, the T allele attenuates the binding of miR-453, which might lead to a reduced miRNA-mediated ESR1 repression, in consequence higher ESR1 protein levels and an increased breast cancer risk. Thus, the breast cancer protective effect observed for the C allele in premenopausal women is biologically reasonable. The analysis of large study populations in multicentre collaboration will be needed to verify the association and answer questions regarding the possible impact of this variant on therapeutic and clinical outcome.
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Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2.
Shahana Ahmed, Gilles Thomas, Maya Ghoussaini, Catherine S Healey, Manjeet K Humphreys, Radka Platte, Jonathan Morrison, Melanie Maranian, Karen A Pooley, Robert Luben, Diana Eccles, D Gareth Evans, Olivia Fletcher, Nichola Johnson, Isabel Dos Santos Silva, Julian Peto, Michael R Stratton, Nazneen Rahman, Kevin Jacobs, Ross Prentice, Garnet L Anderson, Aleksandar Rajkovic, J David Curb, Regina G Ziegler, Christine D Berg, Saundra S Buys, Catherine A McCarty, Heather Spencer Feigelson, Eugenia E Calle, Michael J Thun, W Ryan Diver, Stig Bojesen, Børge G Nordestgaard, Henrik Flyger, Thilo Dörk, Peter Schürmann, Peter Hillemanns, Johann H Karstens, Natalia V Bogdanova, Natalia N Antonenkova, Iosif V Zalutsky, Marina Bermisheva, Sardana Fedorova, Elza Khusnutdinova, , Daehee Kang, Keun-Young Yoo, Dong Young Noh, Sei-Hyun Ahn, Peter Devilee, Christi J van Asperen, R A E M Tollenaar, Caroline Seynaeve, Montserrat Garcia-Closas, Jolanta Lissowska, Louise Brinton, Beata Peplonska, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, John L Hopper, Melissa C Southey, Letitia Smith, Amanda B Spurdle, Marjanka K Schmidt, Annegien Broeks, Richard R van Hien, Sten Cornelissen, Roger L Milne, Gloria Ribas, Anna González-Neira, Javier Benitez, Rita K Schmutzler, Barbara Burwinkel, Claus R Bartram, Alfons Meindl, Hiltrud Brauch, Christina Justenhoven, Ute Hamann, Jenny Chang-Claude, Rebecca Hein, Shan Wang-Gohrke, Annika Lindblom, Sara Margolin, Arto Mannermaa, Veli-Matti Kosma, Vesa Kataja, Janet E Olson, Xianshu Wang, Zachary Fredericksen, Graham G Giles, Gianluca Severi, Laura Baglietto, Dallas R English, Susan E Hankinson, David G Cox, Peter Kraft, Lars J Vatten, Kristian Hveem, Merethe Kumle, Alice Sigurdson, Michele Doody, Parveen Bhatti, Bruce H Alexander, Maartje J Hooning, Ans M W van den Ouweland, Rogier A Oldenburg, Mieke Schutte, Per Hall, Kamila Czene, Jianjun Liu, Yuqing Li, Angela Cox, Graeme Elliott, Ian Brock, Malcolm W R Reed, Chen-Yang Shen, Jyh-Cherng Yu, Giu-Cheng Hsu, Shou-Tung Chen, Hoda Anton-Culver, Argyrios Ziogas, Irene L Andrulis, Julia A Knight, Jonathan Beesley, Ellen L Goode, Fergus Couch, Georgia Chenevix-Trench, Robert N Hoover, Bruce A J Ponder, David J Hunter, Paul D P Pharoah, Alison M Dunning, Stephen J Chanock, Douglas F Easton.
Nat. Genet.
PUBLISHED: 02-03-2009
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Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08-1.13, P = 4.1 x 10(-23)) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92-0.97, P = 1.4 x 10(-8)). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.
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Polymorphisms in BRCA2 resulting in aberrant codon-usage and their analysis on familial breast cancer risk.
Breast Cancer Res. Treat.
PUBLISHED: 01-08-2009
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Mutations in BRCA1 and BRCA2 are associated with increased breast cancer risk. While numerous non-synonymous SNPs in BRCA1/2 have been investigated for breast cancer risk, the impact of synonymous SNPs has not been studied so far. Recently, it has been reported that synonymous SNPs leading to an aberration from the preferred codon-usage can have functional effects and consequently be associated with disease. This motivated us to search for SNPs with the tendency to differential codon-usage in BRCA1/BRCA2. Based on defined criteria, two codon-usage-changing variants, Ser455Ser (1365A > G) and Ser2414Ser (7242A > G), were detected in BRCA2, whereas no such variant could be identified in BRCA1. We investigated the impact of these variants on breast cancer risk in a large case-control study. However, both SNPs, BRCA2 Ser2414Ser (7242A > G) and Ser455Ser (1365A > G), showed no association with breast cancer risk. This indicates that these codon-usage-changing SNPs have no major impact on familial breast cancer risk.
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Analysis of 30 putative BRCA1 splicing mutations in hereditary breast and ovarian cancer families identifies exonic splice site mutations that escape in silico prediction.
PLoS ONE
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Screening for pathogenic mutations in breast and ovarian cancer genes such as BRCA1/2, CHEK2 and RAD51C is common practice for individuals from high-risk families. However, test results may be ambiguous due to the presence of unclassified variants (UCV) in the concurrent absence of clearly cancer-predisposing mutations. Especially the presence of intronic or exonic variants within these genes that possibly affect proper pre-mRNA processing poses a challenge as their functional implications are not immediately apparent. Therefore, it appears necessary to characterize potential splicing UCV and to develop appropriate classification tools. We investigated 30 distinct BRCA1 variants, both intronic and exonic, regarding their spliceogenic potential by commonly used in silico prediction algorithms (HSF, MaxEntScan) along with in vitro transcript analyses. A total of 25 variants were identified spliceogenic, either causing/enhancing exon skipping or activation of cryptic splice sites, or both. Except from a single intronic variant causing minor effects on BRCA1 pre-mRNA processing in our analyses, 23 out of 24 intronic variants were correctly predicted by MaxEntScan, while HSF was less accurate in this cohort. Among the 6 exonic variants analyzed, 4 severely impair correct pre-mRNA processing, while the remaining two have partial effects. In contrast to the intronic alterations investigated, only half of the spliceogenic exonic variants were correctly predicted by HSF and/or MaxEntScan. These data support the idea that exonic splicing mutations are commonly disease-causing and concurrently prone to escape in silico prediction, hence necessitating experimental in vitro splicing analysis.
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High expression of crystallin ?B represents an independent molecular marker for unfavourable ovarian cancer patient outcome and impairs TRAIL- and cisplatin-induced apoptosis in human ovarian cancer cells.
Int. J. Cancer
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Dysregulated apoptotic pathways are regarded as major reasons for chemoresistance development as a particular challenge in ovarian cancer therapy. In search of molecular factors affecting human ovarian cancer cell apoptosis and, consequently, patient survival, we examined tumors of 103 platinum-/taxane-treated ovarian cancer patients by mRNA-array hybridization, qPCR, and immunohistochemistry. We identified high expression of crystallin ?B (CRYAB), a proposed negative regulator of tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. By Kaplan Meier analysis, this factor turned out to be significantly associated with poor patient outcome [overall survival (OS) p = 0.001, recurrence-free survival (RFS) p = 0.003]. Elevated hazard ratios (HR) were estimated with regard to OS (HR = 2.11, 95% CI 1.10-4.06) and RFS (HR = 1.92, 95% CI 1.07-3.47) in multivariable analyses. These associations were confirmed in independent, publicly available mRNA data comprising 431 patients for OS (p < 0.001) and 413 for RFS (p < 0.001). Our findings were validated by studying apoptotic events in cultured human ovarian cancer cells which were stably transfected to express elevated CRYAB levels. These data emphasized the crucial role of CRYAB in human ovarian cancer biology since TRAIL- as well as cisplatin-induced apoptosis was significantly impaired as a function of enhanced CRYAB expression. Taken together, we identified CRYAB as an independent biomarker for unfavourable outcome of human ovarian cancer patients. Since TRAIL is currently tested as anti-cancer drug and large proportions of the present patient cohort displayed low CRYAB levels in their tumors, CRYAB may enable the selection of patient subgroups benefiting most from TRAIL-containing therapy.
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The risk of contralateral breast cancer in patients from BRCA1/2 negative high risk families as compared to patients from BRCA1 or BRCA2 positive families: a retrospective cohort study.
Breast Cancer Res.
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ABSTRACT: INTRODUCTION: While it has been reported that the risk of contralateral breast cancer in patients from BRCA1 or BRCA2 positive families is elevated, little is known about contralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations. METHODS: A retrospective, multicenter cohort study was performed from 1996 to 2011 and comprised 6,235 women with unilateral breast cancer from 6,230 high risk families that had tested positive for BRCA1 (n = 1,154) or BRCA2 (n = 575) mutations or tested negative (n = 4,501). Cumulative contralateral breast cancer risks were calculated using the Kaplan-Meier product-limit method and were compared between groups using the log-rank test. Cox regression analysis was applied to assess the impact of the age at first breast cancer and the familial history stratified by mutation status. RESULTS: The cumulative risk of contralateral breast cancer 25 years after first breast cancer was 44.1% (95%CI, 37.6% to 50.6%) for patients from BRCA1 positive families, 33.5% (95%CI, 22.4% to 44.7%) for patients from BRCA2 positive families and 17.2% (95%CI, 14.5% to 19.9%) for patients from families that tested negative for BRCA1/2 mutations. Younger age at first breast cancer was associated with a higher risk of contralateral breast cancer. For women who had their first breast cancer before the age of 40 years, the cumulative risk of contralateral breast cancer after 25 years was 55.1% for BRCA1, 38.4% for BRCA2, and 28.4% for patients from BRCA1/2 negative families. If the first breast cancer was diagnosed at the age of 50 or later, 25-year cumulative risks were 21.6% for BRCA1, 15.5% for BRCA2, and 12.9% for BRCA1/2 negative families. CONCLUSIONS: Contralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations is similar to the risk in patients with sporadic breast cancer. Thus, the mutation status should guide decision making for contralateral mastectomy.
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A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11.
Afshan Siddiq, Fergus J Couch, Gary K Chen, Sara Lindstrom, Diana Eccles, Robert C Millikan, Kyriaki Michailidou, Daniel O Stram, Lars Beckmann, Suhn Kyong Rhie, Christine B Ambrosone, Kristiina Aittomäki, Pilar Amiano, Carmel Apicella, , Laura Baglietto, Elisa V Bandera, Matthias W Beckmann, Christine D Berg, Leslie Bernstein, Carl Blomqvist, Hiltrud Brauch, Louise Brinton, Quang M Bui, Julie E Buring, Saundra S Buys, Daniele Campa, Jane E Carpenter, Daniel I Chasman, Jenny Chang-Claude, Constance Chen, Francoise Clavel-Chapelon, Angela Cox, Simon S Cross, Kamila Czene, Sandra L Deming, Robert B Diasio, W Ryan Diver, Alison M Dunning, Lorraine Durcan, Arif B Ekici, Peter A Fasching, Heather Spencer Feigelson, Laura Fejerman, Jonine D Figueroa, Olivia Fletcher, Dieter Flesch-Janys, Mia M Gaudet, Susan M Gerty, Jorge L Rodriguez-Gil, Graham G Giles, Carla H van Gils, Andrew K Godwin, Nikki Graham, Dario Greco, Per Hall, Susan E Hankinson, Arndt Hartmann, Rebecca Hein, Judith Heinz, Robert N Hoover, John L Hopper, Jennifer J Hu, Scott Huntsman, Sue A Ingles, Astrid Irwanto, Claudine Isaacs, Kevin B Jacobs, Esther M John, Christina Justenhoven, Rudolf Kaaks, Laurence N Kolonel, Gerhard A Coetzee, Mark Lathrop, Loic Le Marchand, Adam M Lee, I-Min Lee, Timothy Lesnick, Peter Lichtner, Jianjun Liu, Eiliv Lund, Enes Makalic, Nicholas G Martin, Catriona A McLean, Hanne Meijers-Heijboer, Alfons Meindl, Penelope Miron, Kristine R Monroe, Grant W Montgomery, Bertram Müller-Myhsok, Stefan Nickels, Sarah J Nyante, Curtis Olswold, Kim Overvad, Domenico Palli, Daniel J Park, Julie R Palmer, Harsh Pathak, Julian Peto, Paul Pharoah, Nazneen Rahman, Fernando Rivadeneira, Daniel F Schmidt, Rita K Schmutzler, Susan Slager, Melissa C Southey, Kristen N Stevens, Hans-Peter Sinn, Michael F Press, Eric Ross, Elio Riboli, Paul M Ridker, Fredrick R Schumacher, Gianluca Severi, Isabel Dos Santos Silva, Jennifer Stone, Malin Sund, William J Tapper, Michael J Thun, Ruth C Travis, Clare Turnbull, André G Uitterlinden, Quinten Waisfisz, Xianshu Wang, Zhaoming Wang, Joellen Weaver, Rüdiger Schulz-Wendtland, Lynne R Wilkens, David Van Den Berg, Wei Zheng, Regina G Ziegler, Elad Ziv, Heli Nevanlinna, Douglas F Easton, David J Hunter, Brian E Henderson, Stephen J Chanock, Montserrat Garcia-Closas, Peter Kraft, Christopher A Haiman, Celine M Vachon.
Hum. Mol. Genet.
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Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ? 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
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BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk.
J. Med. Genet.
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Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p.Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer.
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Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC).
Rebecca Hein, Melanie Maranian, John L Hopper, Miroslaw K Kapuscinski, Melissa C Southey, Daniel J Park, Marjanka K Schmidt, Annegien Broeks, Frans B L Hogervorst, H Bas Bueno-de-Mesquita, H Bas Bueno-de-Mesquit, Kenneth R Muir, Artitaya Lophatananon, Suthee Rattanamongkongul, Puttisak Puttawibul, Peter A Fasching, Alexander Hein, Arif B Ekici, Matthias W Beckmann, Olivia Fletcher, Nichola Johnson, Isabel Dos Santos Silva, Julian Peto, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Nicola Miller, Frederick Marmee, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Emilie Cordina-Duverger, Florence Menegaux, Thérèse Truong, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, Roger L Milne, Jose Ignacio Arias Perez, M Pilar Zamora, Javier Benitez, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina A Clarke, Hermann Brenner, Heiko Muller, Volker Arndt, Christa Stegmaier, Nazneen Rahman, Sheila Seal, Clare Turnbull, Anthony Renwick, Alfons Meindl, Sarah Schott, Claus R Bartram, Rita K Schmutzler, Hiltrud Brauch, Ute Hamann, Yon-Dschun Ko, , Shan Wang-Gohrke, Thilo Dörk, Peter Schürmann, Johann H Karstens, Peter Hillemanns, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, Natalia V Bogdanova, Iosif V Zalutsky, Natalia N Antonenkova, Marina Bermisheva, Darya Prokovieva, Albina Farahtdinova, Elza Khusnutdinova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana Hartikainen, Xiaoqing Chen, Jonathan Beesley, Diether Lambrechts, Hui Zhao, Patrick Neven, Hans Wildiers, Stefan Nickels, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Fergus J Couch, Janet E Olson, Xianshu Wang, Zachary Fredericksen, Graham G Giles, Laura Baglietto, Catriona A McLean, Gianluca Severi, Kenneth Offit, Mark Robson, Mia M Gaudet, Joseph Vijai, Grethe Grenaker Alnæs, Vessela Kristensen, Anne-Lise Børresen-Dale, Esther M John, Alexander Miron, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Jonine D Figueroa, Montserrat Garcia-Closas, Jolanta Lissowska, Mark E Sherman, Maartje Hooning, John W M Martens, Caroline Seynaeve, Margriet Collée, Per Hall, Keith Humpreys, Kamila Czene, Jianjun Liu, Angela Cox, Ian W Brock, Simon S Cross, Malcolm W R Reed, Shahana Ahmed, Maya Ghoussaini, Paul D P Pharoah, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Anna Jakubowska, Katarzyna Jaworska, Katarzyna Durda, Elzbieta Złowocka, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Chen-Yang Shen, Jyh-Cherng Yu, Huan-Ming Hsu, Ming-Feng Hou, Nick Orr, Minouk Schoemaker, Alan Ashworth, Anthony Swerdlow, Amy Trentham-Dietz, Polly A Newcomb, Linda Titus, Kathleen M Egan, Georgia Chenevix-Trench, Antonis C Antoniou, Manjeet K Humphreys, Jonathan Morrison, Jenny Chang-Claude, Douglas F Easton, Alison M Dunning.
PLoS ONE
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The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.
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9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: evidence from the Breast Cancer Association Consortium.
Helen Warren, Frank Dudbridge, Olivia Fletcher, Nick Orr, Nichola Johnson, John L Hopper, Carmel Apicella, Melissa C Southey, Maryam Mahmoodi, Marjanka K Schmidt, Annegien Broeks, Sten Cornelissen, Linda M Braaf, Kenneth R Muir, Artitaya Lophatananon, Arkom Chaiwerawattana, Surapon Wiangnon, Peter A Fasching, Matthias W Beckmann, Arif B Ekici, Ruediger Schulz-Wendtland, Elinor J Sawyer, Ian Tomlinson, Michael Kerin, Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Claire Mulot, Stig E Bojesen, Sune F Nielsen, Henrik Flyger, Børge G Nordestgaard, Roger L Milne, Javier Benitez, Jose-Ignacio Arias-Perez, M Pilar Zamora, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina Clarke Dur, Hermann Brenner, Heiko Muller, Volker Arndt, Anne Langheinz, Alfons Meindl, Michael Golatta, Claus R Bartram, Rita K Schmutzler, Hiltrud Brauch, Christina Justenhoven, Thomas Brüning, , Jenny Chang-Claude, Shan Wang-Gohrke, Ursula Eilber, Thilo Dörk, Peter Schürmann, Michael Bremer, Peter Hillemanns, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Natalia Bogdanova, Natalia Antonenkova, Yuriy Rogov, Marina Bermisheva, Darya Prokofyeva, Guzel Zinnatullina, Elza Khusnutdinova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Veli-Matti Kosma, Jaana M Hartikainen, Vesa Kataja, Georgia Chenevix-Trench, Jonathan Beesley, Xiaoqing Chen, Diether Lambrechts, Ann Smeets, Robert Paridaens, Caroline Weltens, Dieter Flesch-Janys, Katharina Buck, Sabine Behrens, Paolo Peterlongo, Loris Bernard, Siranoush Manoukian, Paolo Radice, Fergus J Couch, Celine Vachon, Xianshu Wang, Janet Olson, Graham Giles, Laura Baglietto, Cariona A McLean, Gianluca Severi, Esther M John, Alexander Miron, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L Andrulis, Julia A Knight, Anna Marie Mulligan, Nayana Weerasooriya, Peter Devilee, Robert A E M Tollenaar, John W M Martens, Caroline M Seynaeve, Maartje J Hooning, Antoinette Hollestelle, Agnes Jager, Madeleine M A Tilanus-Linthorst, Per Hall, Kamila Czene, Jianjun Liu, Jingmei Li, Angela Cox, Simon S Cross, Ian W Brock, Malcolm W R Reed, Paul Pharoah, Fiona M Blows, Alison M Dunning, Maya Ghoussaini, Alan Ashworth, Anthony Swerdlow, Michael Jones, Minouk Schoemaker, Douglas F Easton, Manjeet Humphreys, Qin Wang, Julian Peto, Isabel Dos-Santos-Silva.
Cancer Epidemiol. Biomarkers Prev.
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Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).
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Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2.
Tomas Kirchhoff, Mia M Gaudet, Antonis C Antoniou, Lesley McGuffog, Manjeet K Humphreys, Alison M Dunning, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Sei-Hyun Ahn, Thilo Dörk, Peter Schürmann, Johann H Karstens, Peter Hillemanns, Fergus J Couch, Janet Olson, Celine Vachon, Xianshu Wang, Angela Cox, Ian Brock, Graeme Elliott, Malcolm W R Reed, Barbara Burwinkel, Alfons Meindl, Hiltrud Brauch, Ute Hamann, Yon-Dschun Ko, , Annegien Broeks, Marjanka K Schmidt, Laura J van 't Veer, Linde M Braaf, Nichola Johnson, Olivia Fletcher, Lorna Gibson, Julian Peto, Clare Turnbull, Sheila Seal, Anthony Renwick, Nazneen Rahman, Pei-Ei Wu, Jyh-Cherng Yu, Chia-Ni Hsiung, Chen-Yang Shen, Melissa C Southey, John L Hopper, Fleur Hammet, Thijs Van Dorpe, Anne-Sophie Dieudonné, Sigrid Hatse, Diether Lambrechts, Irene L Andrulis, Natalia Bogdanova, Natalia Antonenkova, Juri I Rogov, Daria Prokofieva, Marina Bermisheva, Elza Khusnutdinova, Christi J van Asperen, Robert A E M Tollenaar, Maartje J Hooning, Peter Devilee, Sara Margolin, Annika Lindblom, Roger L Milne, José Ignacio Arias, M Pilar Zamora, Javier Benitez, Gianluca Severi, Laura Baglietto, Graham G Giles, Amanda B Spurdle, Jonathan Beesley, Xiaoqing Chen, Helene Holland, Sue Healey, Shan Wang-Gohrke, Jenny Chang-Claude, Arto Mannermaa, Veli-Matti Kosma, Jaana Kauppinen, Vesa Kataja, Bjarni A Agnarsson, Maria A Caligo, Andrew K Godwin, Heli Nevanlinna, Tuomas Heikkinen, Zachary Fredericksen, Noralane Lindor, Katherine L Nathanson, Susan M Domchek, Niklas Loman, Per Karlsson, Marie Stenmark Askmalm, Beatrice Melin, Anna von Wachenfeldt, Frans B L Hogervorst, Martijn Verheus, Matti A Rookus, Caroline Seynaeve, Rogier A Oldenburg, Marjolijn J Ligtenberg, Margreet G E M Ausems, Cora M Aalfs, Hans J P Gille, Juul T Wijnen, Encarna B Gomez Garcia, Susan Peock, Margaret Cook, Clare T Oliver, Debra Frost, Craig Luccarini, Gabriella Pichert, Rosemarie Davidson, Carol Chu, Diana Eccles, Kai-Ren Ong, Jackie Cook, Fiona Douglas, Shirley Hodgson, D Gareth Evans, Rosalind Eeles, Bert Gold, Paul D P Pharoah, Kenneth Offit, Georgia Chenevix-Trench, Douglas F Easton.
PLoS ONE
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Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR)?=?1.03, 95% CI 1.00-1.06, p?=?0.023). There was evidence for heterogeneity in the ORs among studies (I(2)?=?49.3%; p?=?<0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR?=?0.89, 95%CI 0.80-1.00, p?=?0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
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A 24-color metaphase-based radiation assay discriminates heterozygous BRCA2 mutation carriers from controls by chromosomal radiosensitivity.
Breast Cancer Res. Treat.
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Numerous allelic variants identified in the familial breast cancer and DNA repair genes BRCA1 and BRCA2 are of unknown impact on protein function or clinical relevance, referred to as unclassified variants (UCV). Lymphocytes from pathogenic BRCA1/2 mutation carriers exhibit an increased level of chromosomal damage after irradiation. We established a radiation assay for the discrimination of pathogenic BRCA2 variants versus controls based on the level of chromosomal damage upon irradiation (p < 0.001). As a consequence, lymphocytes from UCV carriers could be separated into two distinct groups with normal or diminished DNA double strand break repair capacity. Our results suggested that all five UCV tested were benign and that one family carried a putative mutation in an as yet undetected DNA-repair gene. Thus, our test may serve as a valuable tool that aids the classification of BRCA2 UCV, but very likely also of BRCA1 UCV or aberrations in other genes involved in the DNA-repair system.
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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.