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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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Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium.
Roger L Milne, Barbara Burwinkel, Kyriaki Michailidou, Jose-Ignacio Arias-Perez, M Pilar Zamora, Primitiva Menéndez-Rodríguez, David Hardisson, Marta Mendiola, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Joe Dennis, Qin Wang, Manjeet K Bolla, Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk Schoemaker, Yon-Dschun Ko, Hiltrud Brauch, Ute Hamann, , Irene L Andrulis, Julia A Knight, Gord Glendon, Sandrine Tchatchou, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Kazuo Tajima, Jingmei Li, Judith S Brand, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Diether Lambrechts, Gilian Peuteman, Marie-Rose Christiaens, Ann Smeets, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska-Bieniek, Katazyna Durda, Mikael Hartman, Miao Hui, Wei Yen Lim, Ching Wan Chan, Federick Marme, Rongxi Yang, Peter Bugert, Annika Lindblom, Sara Margolin, Montserrat Garcia-Closas, Stephen J Chanock, Jolanta Lissowska, Jonine D Figueroa, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, Maartje J Hooning, Mieke Kriege, Ans M W van den Ouweland, Linetta B Koppert, Olivia Fletcher, Nichola Johnson, Isabel Dos-Santos-Silva, Julian Peto, Wei Zheng, Sandra Deming-Halverson, Martha J Shrubsole, Jirong Long, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Angela Cox, Simon S Cross, Malcolm W R Reed, Marjanka K Schmidt, Annegien Broeks, Sten Cornelissen, Linde Braaf, Daehee Kang, Ji-Yeob Choi, Sue K Park, Dong-Young Noh, Jacques Simard, Martine Dumont, Mark S Goldberg, France Labrèche, Peter A Fasching, Alexander Hein, Arif B Ekici, Matthias W Beckmann, Paolo Radice, Paolo Peterlongo, Jacopo Azzollini, Monica Barile, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Nicola Miller, John L Hopper, Daniel F Schmidt, Enes Makalic, Melissa C Southey, Soo Hwang Teo, Cheng Har Yip, Kavitta Sivanandan, Wan-Ting Tay, Chen-Yang Shen, Chia-Ni Hsiung, Jyh-Cherng Yu, Ming-Feng Hou, Pascal Guénel, Thérèse Truong, Marie Sanchez, Claire Mulot, William Blot, Qiuyin Cai, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Anna H Wu, Chiu-Chen Tseng, David Van Den Berg, Daniel O Stram, Natalia Bogdanova, Thilo Dörk, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Ben Zhang, Fergus J Couch, Amanda E Toland, Drakoulis Yannoukakos, Suleeporn Sangrajrang, James McKay, Xianshu Wang, Janet E Olson, Celine Vachon, Kristen Purrington, Gianluca Severi, Laura Baglietto, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Peter Devilee, Robert A E M Tollenaar, Caroline Seynaeve, Kamila Czene, Mikael Eriksson, Keith Humphreys, Hatef Darabi, Shahana Ahmed, Mitul Shah, Paul D P Pharoah, Per Hall, Graham G Giles, Javier Benitez, Alison M Dunning, Georgia Chenevix-Trench, Douglas F Easton.
Hum. Mol. Genet.
PUBLISHED: 06-18-2014
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Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
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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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Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.
John R B Perry, Felix Day, Cathy E Elks, Patrick Sulem, Deborah J Thompson, Teresa Ferreira, Chunyan He, Daniel I Chasman, Tonu Esko, Gudmar Thorleifsson, Eva Albrecht, Wei Q Ang, Tanguy Corre, Diana L Cousminer, Bjarke Feenstra, Nora Franceschini, Andrea Ganna, Andrew D Johnson, Sanela Kjellqvist, Kathryn L Lunetta, George McMahon, Ilja M Nolte, Lavinia Paternoster, Eleonora Porcu, Albert V Smith, Lisette Stolk, Alexander Teumer, Natalia Tšernikova, Emmi Tikkanen, Sheila Ulivi, Erin K Wagner, Najaf Amin, Laura J Bierut, Enda M Byrne, Jouke-Jan Hottenga, Daniel L Koller, Massimo Mangino, Tune H Pers, Laura M Yerges-Armstrong, Jing Hua Zhao, Irene L Andrulis, Hoda Anton-Culver, Femke Atsma, Stefania Bandinelli, Matthias W Beckmann, Javier Benitez, Carl Blomqvist, Stig E Bojesen, Manjeet K Bolla, Bernardo Bonanni, Hiltrud Brauch, Hermann Brenner, Julie E Buring, Jenny Chang-Claude, Stephen Chanock, Jinhui Chen, Georgia Chenevix-Trench, J Margriet Collée, Fergus J Couch, David Couper, Andrea D Coviello, Angela Cox, Kamila Czene, Adamo Pio D'adamo, George Davey Smith, Immaculata De Vivo, Ellen W Demerath, Joe Dennis, Peter Devilee, Aida K Dieffenbach, Alison M Dunning, Gudny Eiriksdottir, Johan G Eriksson, Peter A Fasching, Luigi Ferrucci, Dieter Flesch-Janys, Henrik Flyger, Tatiana Foroud, Lude Franke, Melissa E Garcia, Montserrat Garcia-Closas, Frank Geller, Eco E J de Geus, Graham G Giles, Daniel F Gudbjartsson, Vilmundur Gudnason, Pascal Guénel, Suiqun Guo, Per Hall, Ute Hamann, Robin Haring, Catharina A Hartman, Andrew C Heath, Albert Hofman, Maartje J Hooning, John L Hopper, Frank B Hu, David J Hunter, David Karasik, Douglas P Kiel, Julia A Knight, Veli-Matti Kosma, Zoltan Kutalik, Sandra Lai, Diether Lambrechts, Annika Lindblom, Reedik Mägi, Patrik K Magnusson, Arto Mannermaa, Nicholas G Martin, Gisli Masson, Patrick F McArdle, Wendy L McArdle, Mads Melbye, Kyriaki Michailidou, Evelin Mihailov, Lili Milani, Roger L Milne, Heli Nevanlinna, Patrick Neven, Ellen A Nohr, Albertine J Oldehinkel, Ben A Oostra, Aarno Palotie, Munro Peacock, Nancy L Pedersen, Paolo Peterlongo, Julian Peto, Paul D P Pharoah, Dirkje S Postma, Anneli Pouta, Katri Pylkäs, Paolo Radice, Susan Ring, Fernando Rivadeneira, Antonietta Robino, Lynda M Rose, Anja Rudolph, Veikko Salomaa, Serena Sanna, David Schlessinger, Marjanka K Schmidt, Mellissa C Southey, Ulla Sovio, Meir J Stampfer, Doris Stöckl, Anna M Storniolo, Nicholas J Timpson, Jonathan Tyrer, Jenny A Visser, Peter Vollenweider, Henry Völzke, Gérard Waeber, Melanie Waldenberger, Henri Wallaschofski, Qin Wang, Gonneke Willemsen, Robert Winqvist, Bruce H R Wolffenbuttel, Margaret J Wright, , Dorret I Boomsma, Michael J Econs, Kay-Tee Khaw, Ruth J F Loos, Mark I McCarthy, Grant W Montgomery, John P Rice, Elizabeth A Streeten, Unnur Thorsteinsdottir, Cornelia M van Duijn, Behrooz Z Alizadeh, Sven Bergmann, Eric Boerwinkle, Heather A Boyd, Laura Crisponi, Paolo Gasparini, Christian Gieger, Tamara B Harris, Erik Ingelsson, Marjo-Riitta Järvelin, Peter Kraft, Debbie Lawlor, Andres Metspalu, Craig E Pennell, Paul M Ridker, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, David P Strachan, André G Uitterlinden, Nicholas J Wareham, Elisabeth Widén, Marek Zygmunt, Anna Murray, Douglas F Easton, Kari Stefansson, Joanne M Murabito, Ken K Ong.
Nature
PUBLISHED: 05-30-2014
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Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P?
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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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Correlation of DNA methylation levels in blood and saliva DNA in young girls of the LEGACY Girls study.
Epigenetics
PUBLISHED: 04-22-2014
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Many epidemiologic studies of environmental exposures and disease susceptibility measure DNA methylation in white blood cells (WBC). Some studies are also starting to use saliva DNA as it is usually more readily available in large epidemiologic studies. However, little is known about the correlation of methylation between WBC and saliva DNA. We examined DNA methylation in three repetitive elements, Sat2, Alu, and LINE-1, and in four CpG sites, including AHRR (cg23576855, cg05575921), cg05951221 at 2q37.1, and cg11924019 at CYP1A1, in 57 girls aged 6-15 years with blood and saliva collected on the same day. We measured all DNA methylation markers by bisulfite-pyrosequencing, except for Sat2 and Alu, which were measured by the MethyLight assay. Methylation levels measured in saliva DNA were lower than those in WBC DNA, with differences ranging from 2.8% for Alu to 14.1% for cg05575921. Methylation levels for the three repetitive elements measured in saliva DNA were all positively correlated with those in WBC DNA. However, there was a wide range in the Spearman correlations, with the smallest correlation found for Alu (0.24) and the strongest correlation found for LINE-1 (0.73). Spearman correlations for cg05575921, cg05951221, and cg11924019 were 0.33, 0.42, and 0.79, respectively. If these findings are replicated in larger studies, they suggest that, for selected methylation markers (e.g., LINE-1), methylation levels may be highly correlated between blood and saliva, while for others methylation markers, the levels may be more tissue specific. Thus, in studies that differ by DNA source, each interrogated site should be separately examined in order to evaluate the correlation in DNA methylation levels across DNA sources.
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Investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors.
Int. J. Cancer
PUBLISHED: 04-03-2014
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A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (pint ) <1.1 × 10(-3) . None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women ?170 cm (OR = 1.22, p = 0.017), but inversely associated with ER-negative BC risk in women <160 cm (OR = 0.83, p = 0.039, pint = 1.9 × 10(-4) ). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR = 0.85, p = 2.0 × 10(-4) ), and absent in women who had had just one (OR = 0.96, p = 0.19, pint = 6.1 × 10(-4) ). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR = 0.93, p = 2.8 × 10(-5) ), but no association was observed in current smokers (OR = 1.07, p = 0.14, pint = 3.4 × 10(-4) ). In conclusion, recently identified BC susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies.
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Does perceived risk predict breast cancer screening use? Findings from a prospective cohort study of female relatives from the Ontario site of the Breast Cancer Family Registry.
Breast
PUBLISHED: 04-03-2014
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While the relationship between perceived risk and breast cancer screening use has been studied extensively, most studies are cross-sectional. We prospectively examined this relationship among 913 women, aged 25-72 with varying levels of familial breast cancer risk from the Ontario site of the Breast Cancer Family Registry. Associations between perceived lifetime breast cancer risk and subsequent use of mammography, clinical breast examination (CBE) and genetic testing were assessed using logistic regression. Overall, perceived risk did not predict subsequent use of mammography, CBE or genetic testing. Among women at moderate/high familial risk, those reporting a perceived risk greater than 50% were significantly less likely to have a CBE (odds ratio (OR) = 0.52, 95% confidence interval (CI): 0.30-0.91, p = 0.04), and non-significantly less likely to have a mammogram (OR = 0.70, 95% CI: 0.40-1.20, p = 0.70) or genetic test (OR = 0.61, 95% CI: 0.34-1.10, p = 0.09) compared to women reporting a perceived risk of 50%. In contrast, among women at low familial risk, those reporting a perceived risk greater than 50% were non-significantly more likely to have a mammogram (OR = 1.13, 95% CI: 0.59-2.16, p = 0.78), CBE (OR = 1.11, 95% CI: 0.63-1.95, p = 0.74) or genetic test (OR = 1.29, 95% CI: 0.50-3.33, p = 0.35) compared to women reporting a perceived risk of 50%. Perceived risk did not significantly predict screening use overall, however this relationship may be moderated by level of familial risk. Results may inform risk education and management strategies for women with varying levels of familial breast cancer risk.
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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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Human subjects protection: an event monitoring committee for research studies of girls from breast cancer families.
J Adolesc Health
PUBLISHED: 03-18-2014
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Researchers must monitor the safety of research participants, particularly in studies involving children and adolescents. Yet, there is limited guidance for the development and implementation of oversight committees for psychosocial, behavioral intervention, and observational studies.
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Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.
Maya Ghoussaini, Stacey L Edwards, Kyriaki Michailidou, Silje Nord, Richard Cowper-Sal Lari, Kinjal Desai, Siddhartha Kar, Kristine M Hillman, Susanne Kaufmann, Dylan M Glubb, Jonathan Beesley, Joe Dennis, Manjeet K Bolla, Qin Wang, Ed Dicks, Qi Guo, Marjanka K Schmidt, Mitul Shah, Robert Luben, Judith Brown, Kamila Czene, Hatef Darabi, Mikael Eriksson, Daniel Klevebring, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Diether Lambrechts, Bernard Thienpont, Patrick Neven, Hans Wildiers, Annegien Broeks, Laura J Van't Veer, Emiel J Th Rutgers, Fergus J Couch, Janet E Olson, Emily Hallberg, Celine Vachon, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Julian Peto, Isabel Dos-Santos-Silva, Lorna Gibson, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Per Hall, Jingmei Li, Jianjun Liu, Keith Humphreys, Daehee Kang, Ji-Yeob Choi, Sue K Park, Dong-Young Noh, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Yasushi Yatabe, Pascal Guénel, Thérèse Truong, Florence Menegaux, Marie Sanchez, Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Anna H Wu, Chiu-Chen Tseng, David Van Den Berg, Daniel O Stram, Javier Benitez, M Pilar Zamora, Jose Ignacio Arias Perez, Primitiva Menéndez, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Qiuyin Cai, Angela Cox, Simon S Cross, Malcolm W R Reed, Irene L Andrulis, Julia A Knight, Gord Glendon, Sandrine Tchatchou, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Annika Lindblom, Sara Margolin, Soo Hwang Teo, Cheng Har Yip, Daphne S C Lee, Tien Y Wong, Maartje J Hooning, John W M Martens, J Margriet Collée, Carolien H M van Deurzen, John L Hopper, Melissa C Southey, Helen Tsimiklis, Miroslav K Kapuscinski, Chen-Yang Shen, Pei-Ei Wu, Jyh-Cherng Yu, Shou-Tung Chen, Grethe Grenaker Alnæs, Anne-Lise Borresen-Dale, Graham G Giles, Roger L Milne, Catriona McLean, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Mikael Hartman, Hui Miao, Shaik Ahmad Bin Syed Buhari, Yik Ying Teo, Peter A Fasching, Lothar Haeberle, Arif B Ekici, Matthias W Beckmann, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk J Schoemaker, Montserrat Garcia-Closas, Jonine Figueroa, Stephen J Chanock, Jolanta Lissowska, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Koto, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Sara Volorio, Thilo Dörk, Natalia V Bogdanova, Sonja Helbig, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Peter Devilee, Robert A E M Tollenaar, Caroline Seynaeve, Christi J van Asperen, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Susan Slager, Amanda E Toland, Christine B Ambrosone, Drakoulis Yannoukakos, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Ute Hamann, Diana Torres, Wei Zheng, Jirong Long, Hoda Anton-Culver, Susan L Neuhausen, Craig Luccarini, Caroline Baynes, Shahana Ahmed, Mel Maranian, Catherine S Healey, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Nuria Alvarez, Daniel Herrero, Daniel C Tessier, Daniel Vincent, Francois Bacot, Ines de Santiago, Jason Carroll, Carlos Caldas, Melissa A Brown, Mathieu Lupien, Vessela N Kristensen, Paul D P Pharoah, Georgia Chenevix-Trench, Juliet D French, Douglas F Easton, Alison M Dunning, .
Nat Commun
PUBLISHED: 03-12-2014
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GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.
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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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2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy.
Jingmei Li, Linda S Lindström, Jia N Foo, Sajjad Rafiq, Marjanka K Schmidt, Paul D P Pharoah, Kyriaki Michailidou, Joe Dennis, Manjeet K Bolla, Qin Wang, Laura J van 't Veer, Sten Cornelissen, Emiel Rutgers, Melissa C Southey, Carmel Apicella, Gillian S Dite, John L Hopper, Peter A Fasching, Lothar Haeberle, Arif B Ekici, Matthias W Beckmann, Carl Blomqvist, Taru A Muranen, Kristiina Aittomäki, Annika Lindblom, Sara Margolin, Arto Mannermaa, Veli-Matti Kosma, Jaana M Hartikainen, Vesa Kataja, Georgia Chenevix-Trench, , Kelly-Anne Phillips, Sue-Anne McLachlan, Diether Lambrechts, Bernard Thienpont, Ann Smeets, Hans Wildiers, Jenny Chang-Claude, Dieter Flesch-Janys, Petra Seibold, Anja Rudolph, Graham G Giles, Laura Baglietto, Gianluca Severi, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Vessela Kristensen, Grethe I Grenaker Alnæs, Anne-Lise Borresen-Dale, Silje Nord, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L Andrulis, Julia A Knight, Gord Glendon, Sandrine Tchatchou, Peter Devilee, Robert Tollenaar, Caroline Seynaeve, Maartje Hooning, Mieke Kriege, Antoinette Hollestelle, Ans van den Ouweland, Yi Li, Ute Hamann, Diana Torres, Hans U Ulmer, Thomas Rüdiger, Chen-Yang Shen, Chia-Ni Hsiung, Pei-Ei Wu, Shou-Tung Chen, Soo Hwang Teo, Nur Aishah Mohd Taib, Cheng Har Yip, Gwo Fuang Ho, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Kazuo Tajima, Daehee Kang, Ji-Yeob Choi, Sue K Park, Keun-Young Yoo, Tom Maishman, William J Tapper, Alison Dunning, Mitul Shah, Robert Luben, Judith Brown, Chiea Chuen Khor, Diana M Eccles, Heli Nevanlinna, Douglas Easton, Keith Humphreys, Jianjun Liu, Per Hall, Kamila Czene.
Nat Commun
PUBLISHED: 01-28-2014
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Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment Study (COGS) initiative. We carry out replication using Asian COGS samples (n=522, 53 events) and the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study (n=315, 108 events). Rs4458204_A near CCL20 (2q36.3) is found to be associated with breast cancer-specific death at a genome-wide significant level (n=2,641, 440 events, combined allelic hazard ratio (HR)=1.81 (1.49-2.19); P for trend=1.90 × 10(-9)). Such survival-associated variants can represent ideal targets for tailored therapeutics, and may also enhance our current prognostic prediction capabilities.
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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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IFN-? alters neurotrophic factor expression in T cells isolated from multiple sclerosis patients - implication of novel neurotensin/NTSR1 pathway in neuroprotection.
Am J Transl Res
PUBLISHED: 01-01-2014
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Inflammation in relapsing remitting multiple sclerosis (RRMS) is hypothesized to provide neuroprotective effects via altered cytokine/neurotrophin homeostasis. The distinct neurotrophin production from specific cell populations has not been systematically studied and is likely of high yield in understanding the complex regulation of MS pathogenesis. Here, we describe how the mainstream therapy interferon-? (IFN-?) modulates neurotrophin expression in T cells isolated from RRMS patients and characterize the neuroprotective capabilities of these factors. We utilize SuperArray gene screen technology to investigate the neurotrophin expression profile of T cells. We demonstrate that IFN-? induces an anti-inflammatory cytokine expression pattern in T cells. Additionally, IFN-? upregulates the expression of a novel neurotrophin receptor, the neurotensin high affinity receptor 1 (NTSR1). NTSR1 is expressed in active demyelinating lesions. Furthermore, we demonstrate that the receptor agonist neurotensin is a potent inducer of human neural stem/progenitor cell survival. Our findings highlight the importance of neurotrophin receptors in RRMS and offer insight into disease pathogenesis as well as the mechanisms of action of IFN-?.
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Transplantation of Fas-deficient or wild-type neural stem/progenitor cells (NPCs) is equally efficient in treating experimental autoimmune encephalomyelitis (EAE).
Am J Transl Res
PUBLISHED: 01-01-2014
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Studies have shown that neural stem/progenitor cell (NPC) transplantation is beneficial in experimental autoimmune encephalomyelitis (EAE), an established animal model of multiple sclerosis (MS). It is unclear whether NPCs have the ability to integrate into the host CNS to replace lost cells or if their main mechanism of action is via bystander immunomodulation. Understanding the mechanisms by which NPCs exert their beneficial effects as well as exploring methods to increase post-transplantation survival and differentiation is critical to advancing this treatment strategy. Using the EAE model and Fas-deficient (lpr) NPCs, we investigated the effects of altering the Fas system in NPC transplantation therapy. We show that transplantation of NPCs into EAE mice ameliorates clinical symptoms with greater efficacy than sham treatments regardless of cell type (wt or lpr). NPC transplantation via retro-orbital injections significantly decreased inflammatory infiltrates at the acute time point, with a similar trend at the chronic time point. Both wt and lpr NPCs injected into mice with EAE were able to home to sites of CNS inflammation in the periventricular brain and lumbar spinal cord. Both wt and lpr NPCs have the same capacity for inducing apoptosis of Th1 and Th17 cells, and minimal numbers of NPCs entered the CNS. These cells did not express terminal differentiation markers, suggesting that NPCs exert their effects mainly via bystander peripheral immunomodulation.
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DNA mismatch repair gene MSH6 implicated in determining age at natural menopause.
Hum. Mol. Genet.
PUBLISHED: 12-19-2013
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Length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to about 50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits, to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using Genome-wide Complex Trait Analysis (GCTA). However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P=1.9x10(-9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.
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A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46 450 cases and 42 461 controls from the breast cancer association consortium.
Roger L Milne, Jesús Herranz, Kyriaki Michailidou, Joe Dennis, Jonathan P Tyrer, M Pilar Zamora, José Ignacio Arias-Perez, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Qin Wang, Manjeet K Bolla, Kamila Czene, Mikael Eriksson, Keith Humphreys, Hatef Darabi, Jingmei Li, Hoda Anton-Culver, Susan L Neuhausen, Argyrios Ziogas, Christina A Clarke, John L Hopper, Gillian S Dite, Carmel Apicella, Melissa C Southey, Georgia Chenevix-Trench, , Anthony Swerdlow, Alan Ashworth, Nicholas Orr, Minouk Schoemaker, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Xianshu Wang, Janet E Olson, Celine Vachon, Kristen Purrington, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Alison M Dunning, Mitul Shah, Pascal Guénel, Thérèse Truong, Marie Sanchez, Claire Mulot, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Annika Lindblom, Sara Margolin, Maartje J Hooning, Antoinette Hollestelle, J Margriet Collée, Agnes Jager, Angela Cox, Ian W Brock, Malcolm W R Reed, Peter Devilee, Robert A E M Tollenaar, Caroline Seynaeve, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Martine Dumont, Penny Soucy, Thilo Dörk, Natalia V Bogdanova, Ute Hamann, Asta Försti, Thomas Rüdiger, Hans-Ulrich Ulmer, Peter A Fasching, Lothar Häberle, Arif B Ekici, Matthias W Beckmann, Olivia Fletcher, Nichola Johnson, Isabel Dos Santos Silva, Julian Peto, Paolo Radice, Paolo Peterlongo, Bernard Peissel, Paolo Mariani, Graham G Giles, Gianluca Severi, Laura Baglietto, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Nicola Miller, Federik Marme, Barbara Burwinkel, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Diether Lambrechts, Betul T Yesilyurt, Giuseppe Floris, Karin Leunen, Grethe Grenaker Alnæs, Vessela Kristensen, Anne-Lise Børresen-Dale, Montserrat Garcia-Closas, Stephen J Chanock, Jolanta Lissowska, Jonine D Figueroa, Marjanka K Schmidt, Annegien Broeks, Senno Verhoef, Emiel J Rutgers, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, Fergus J Couch, Amanda E Toland, Drakoulis Yannoukakos, Paul D P Pharoah, Per Hall, Javier Benitez, Nuria Malats, Douglas F Easton.
Hum. Mol. Genet.
PUBLISHED: 11-15-2013
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Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10(-4)) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10(-8). Results from the second analytic approach were consistent with those from the first (P > 10(-10)). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.
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A comparison of methods for EGFR mutation testing in non-small cell lung cancer.
Diagn. Mol. Pathol.
PUBLISHED: 11-07-2013
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EGFR mutation testing of tumor samples is routinely performed to predict sensitivity to treatment with tyrosine kinase inhibitors for patients with non-small cell lung cancer. At least 9 different methodologies are employed in UK laboratories, and the aim of this study was to compare the sensitivity of different methods for the detection of EGFR mutations. Participating laboratories were sent coded samples with varying mutation loads (from 0% to 15%) to be tested for the p.Leu858Arg (p.L858R) missense mutation and c.2235_2249del exon 19 deletion. The p.L858R mutation and deletions within exon 19 of the EGFR gene account for ?90% of mutation-positive cases. The 11 laboratories used their standard testing method(s) and submitted 15 sets of results for the p.L858R samples and 10 for the exon 19 deletion. The p.Leu858Arg (p.L858R) mutation was detected at levels between 1% and 7.5% by Sanger sequencing, pyrosequencing, real-time polymerase chain reaction (PCR), amplification refractory mutation system, and capillary electrophoresis single-strand conformation analysis. The c.2235_2249del mutation was detected at 1% to 5% by fragment size analysis, Sanger sequencing or real-time PCR. A mutation was detected in 24/25 (96%) of the samples tested which contained 5% mutated DNA. The 1% sensitivity claimed for commercial real-time PCR-targeted EGFR tests was achieved and our results show greater sensitivity for the Sanger sequencing and pyrosequencing screening methods compared to the 10% to 20% detection levels cited on clinical diagnostic reports. We conclude that multiple methodologies are suitable for the detection of acquired EGFR mutations.
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Identification of new genetic susceptibility Loci for breast cancer through consideration of gene-environment interactions.
Genet. Epidemiol.
PUBLISHED: 08-12-2013
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Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10(-07) ), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m(2) (OR = 1.26, 95% CI 1.15-1.38) but not in women with a BMI of 30 kg/m(2) or higher (OR = 0.89, 95% CI 0.72-1.11, P for interaction = 3.2 × 10(-05) ). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci.
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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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Diagnostic chest X-rays and breast cancer risk before age 50 years for BRCA1 and BRCA2 mutation carriers.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 07-12-2013
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The effects of low-dose medical radiation on breast cancer risk are uncertain, and few studies have included genetically susceptible women, such as those who carry germline BRCA1 and BRCA2 mutations.
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Evidence of gene-environment interactions between common breast cancer susceptibility loci and established environmental risk factors.
Stefan Nickels, Thérèse Truong, Rebecca Hein, Kristen Stevens, Katharina Buck, Sabine Behrens, Ursula Eilber, Martina Schmidt, Lothar Häberle, Alina Vrieling, Mia Gaudet, Jonine Figueroa, Nils Schoof, Amanda B Spurdle, Anja Rudolph, Peter A Fasching, John L Hopper, Enes Makalic, Daniel F Schmidt, Melissa C Southey, Matthias W Beckmann, Arif B Ekici, Olivia Fletcher, Lorna Gibson, Isabel dos Santos Silva, Julian Peto, Manjeet K Humphreys, Jean Wang, Emilie Cordina-Duverger, Florence Menegaux, Børge G Nordestgaard, Stig E Bojesen, Charlotte Lanng, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina A Clarke, Hermann Brenner, Heiko Muller, Volker Arndt, Christa Stegmaier, Hiltrud Brauch, Thomas Brüning, Volker Harth, , Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Diether Lambrechts, Dominiek Smeets, Patrick Neven, Robert Paridaens, Dieter Flesch-Janys, Nadia Obi, Shan Wang-Gohrke, Fergus J Couch, Janet E Olson, Celine M Vachon, Graham G Giles, Gianluca Severi, Laura Baglietto, Kenneth Offit, Esther M John, Alexander Miron, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Stephen J Chanock, Jolanta Lissowska, Jianjun Liu, Angela Cox, Helen Cramp, Dan Connley, Sabapathy Balasubramanian, Alison M Dunning, Mitul Shah, Amy Trentham-Dietz, Polly Newcomb, Linda Titus, Kathleen Egan, Elizabeth K Cahoon, Preetha Rajaraman, Alice J Sigurdson, Michele M Doody, Pascal Guénel, Paul D P Pharoah, Marjanka K Schmidt, Per Hall, Doug F Easton, Montserrat Garcia-Closas, Roger L Milne, Jenny Chang-Claude.
PLoS Genet.
PUBLISHED: 03-27-2013
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Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4 × 10(-6)) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1 × 10(-4)). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85) in those who drank ? 20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3 × 10(-5)), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.
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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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Perceived risk and adherence to breast cancer screening guidelines among women with a familial history of breast cancer: a review of the literature.
Breast
PUBLISHED: 01-10-2013
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A small positive association has been consistently demonstrated between perceived breast cancer risk and mammography use. Evidence specific to women with familial breast cancer risk has not been previously reviewed.
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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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Prospective association of 25(OH)D with metabolic syndrome.
Clin. Endocrinol. (Oxf)
PUBLISHED: 01-02-2013
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CONTEXT: Vitamin D may play a role in the aetiology of the metabolic syndrome (MetS), yet the majority of previous studies have been cross-sectional, and the limited number of prospective studies has yielded inconsistent results. OBJECTIVE: To examine the prospective association of vitamin D [25-hydroxyvitamin D, 25(OH)D] with MetS in a multi-ethnic cohort of adults in Ontario, Canada. DESIGN: Nondiabetic individuals with pre-existing MetS risk factors were recruited for participation in the PROspective Metabolism and ISlet cell Evaluation (PROMISE) cohort study, a longitudinal study of the determinants of insulin resistance and MetS. METHODS: Of the 654 participants enrolled at baseline, 489 attended a 3-year follow-up visit. There were 301 participants eligible for the analysis of 25(OH)D with incident MetS (age 49·2 ± 9·3 years old, 75·4% female), after excluding 188 (38·5%) prevalent MetS cases at baseline. Longitudinal change in MetS components was assessed in the entire follow-up cohort. RESULTS: There were 76 (15·5%) participants who developed MetS over the 3-years of follow-up. Multivariate logistic regression analyses indicated a decreased risk of MetS at follow-up per standard deviation increase in baseline 25(OH)D after adjustment for sociodemographics, season, baseline and change in supplement use and physical activity and insulin resistance (OR = 0·63, 95% CI 0·44-0·90). Multivariate linear regression analyses revealed a significant inverse association of baseline 25(OH)D with fasting glucose at follow-up (? = -0·0005, P = 0·025). CONCLUSIONS: There was a significant inverse association of baseline 25(OH)D with incident MetS, which may be partly driven by its association with glucose homoeostasis.
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Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction study.
Endocr. Relat. Cancer
PUBLISHED: 01-01-2013
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Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case-control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases (541 lobular) from four genome-wide association studies. The top 1391 SNPs showing P values for interaction (Pint) <3.0 × 10(-3) were selected for replication using pooled case-control data from 11 studies of the Breast Cancer Association Consortium, including 7689 cases (676 lobular) and 9266 controls. Fixed-effects meta-analysis was used to derive combined Pint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 near POMP (combined Pint?8.9 × 10(-6)), two SNPs in SLC25A21 (combined Pint?4.8 × 10(-5)), and three SNPs in PLCG2 (combined Pint?4.5 × 10(-5)). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint?2.7 × 10(-5)), one SNP in CD80 (combined Pint?8.2 × 10(-6)), three SNPs on chr17 near TMEM132E (combined Pint?2.2×10(-6)), and two SNPs on chr18 near SLC25A52 (combined Pint?4.6 × 10(-5)). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling, and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies.
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Accuracy of Self-Reported Screening Mammography Use: Examining Recall among Female Relatives from the Ontario Site of the Breast Cancer Family Registry.
ISRN Oncol
PUBLISHED: 01-01-2013
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Evidence of the accuracy of self-reported mammography use among women with familial breast cancer risk is limited. This study examined the accuracy of self-reported screening mammography dates in a cohort of 1,114 female relatives of breast cancer cases, aged 26 to 73 from the Ontario site of the Breast Cancer Family Registry. Self-reported dates were compared to dates abstracted from imaging reports. Associations between inaccurate recall and subject characteristics were assessed using multinomial regression. Almost all women (95.2% at baseline, 98.5% at year 1, 99.8% at year 2) accurately reported their mammogram use within the previous 12 months. Women at low familial risk (OR = 1.77, 95% CI: 1.00-3.13), who reported 1 or fewer annual visits to a health professional (OR = 1.97, 95% CI: 1.15, 3.39), exhibited a lower perceived breast cancer risk (OR = 1.90, 95% CI: 1.15, 3.15), and reported a mammogram date more than 12 months previous (OR = 5.22, 95% CI: 3.10, 8.80), were significantly more likely to inaccurately recall their mammogram date. Women with varying levels of familial risk are accurate reporters of their mammogram use. These results present the first evidence of self-reported mammography recall accuracy among women with varying levels of familial risk.
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Genetic variants in vitamin d pathway genes and risk of pancreas cancer; results from a population-based case-control study in ontario, Canada.
PLoS ONE
PUBLISHED: 01-01-2013
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Recent studies of 25-hydroxyvitamin D (25(OH)D) levels and pancreas cancer have suggested a potential role of the vitamin D pathway in the etiology of this fatal disease. Variants in vitamin-D related genes are known to affect 25(OH)D levels and function and it is unknown if these variants may influence pancreatic cancer risk. The association between 87 single nucleotide polymorphisms (SNPs) in 11 genes was evaluated within the Ontario Pancreas Cancer Study, a population-based case-control study. Pancreatic cancer cases with pathology confirmed adenocarcinoma were identified from the Ontario Cancer Registry (n?=?628) and controls were identified through random digit dialing (n?=?1193). Age and sex adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated by multivariate logistic regression. SNPs in the CYP24A1, CYP2R1, calcium sensing receptor (CASR), vitamin D binding protein (GC), retinoid X receptor-alpha (RXRA) and megalin (LRP2) genes were significantly associated with pancreas cancer risk. For example, pancreas cancer risk was inversely associated with CYP2R1 rs10741657 (AA versus GG, OR?=?0.70; 95%CI: 0.51-0.95) and positively with CYP24A1 rs6127119 (TT versus CC. OR?=?1.94; 95%CI: 1.28-2.94). None of the associations were statistically significant after adjustment for multiple comparisons. Vitamin D pathway gene variants may be associated with pancreas cancer risk and future studies are needed to understand the possible role of vitamin D in tumorigenesis and may have implications for cancer-prevention strategies.
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Breast cancer risk for noncarriers of family-specific BRCA1 and BRCA2 mutations: findings from the Breast Cancer Family Registry.
J. Clin. Oncol.
PUBLISHED: 10-31-2011
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Women with germline BRCA1 and BRCA2 mutations have five- to 20-fold increased risks of developing breast and ovarian cancer. A recent study claimed that women testing negative for their family-specific BRCA1 or BRCA2 mutation (noncarriers) have a five-fold increased risk of breast cancer. We estimated breast cancer risks for noncarriers by using a population-based sample of patients with breast cancer and their female first-degree relatives (FDRs).
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Prospective associations of vitamin D with ?-cell function and glycemia: the PROspective Metabolism and ISlet cell Evaluation (PROMISE) cohort study.
Diabetes
PUBLISHED: 09-12-2011
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To examine the prospective associations of baseline vitamin D [25-hydroxyvitamin D; 25(OH)D] with insulin resistance (IR), ?-cell function, and glucose homeostasis in subjects at risk for type 2 diabetes.
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Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium.
Jonine D Figueroa, Montserrat Garcia-Closas, Manjeet Humphreys, Radka Platte, John L Hopper, Melissa C Southey, Carmel Apicella, Fleur Hammet, Marjanka K Schmidt, Annegien Broeks, Rob A E M Tollenaar, Laura J Van't Veer, Peter A Fasching, Matthias W Beckmann, Arif B Ekici, Reiner Strick, Julian Peto, Isabel Dos Santos Silva, Olivia Fletcher, Nichola Johnson, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Barbara Burwinkel, Federik Marme, Andreas Schneeweiss, Christof Sohn, Stig Bojesen, Henrik Flyger, Børge G Nordestgaard, Javier Benitez, Roger L Milne, Jose Ignacio Arias, M Pilar Zamora, Hermann Brenner, Heiko Muller, Volker Arndt, Nazneen Rahman, Clare Turnbull, Sheila Seal, Anthony Renwick, Hiltrud Brauch, Christina Justenhoven, Thomas Brüning, , Jenny Chang-Claude, Rebecca Hein, Shan Wang-Gohrke, Thilo Dörk, Peter Schürmann, Michael Bremer, Peter Hillemanns, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, Natalia Bogdanova, Natalia Antonenkova, Yuri I Rogov, Johann Hinrich Karstens, Marina Bermisheva, Darya Prokofieva, Shamil Hanafievich Gantcev, Elza Khusnutdinova, Annika Lindblom, Sara Margolin, Georgia Chenevix-Trench, Jonathan Beesley, Xiaoqing Chen, Arto Mannermaa, Veli-Matti Kosma, Ylermi Soini, Vesa Kataja, Diether Lambrechts, Betul T Yesilyurt, Marie-Rose Chrisiaens, Stéphanie Peeters, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Fergus Couch, Adam M Lee, Robert Diasio, Xianshu Wang, Graham G Giles, Gianluca Severi, Laura Baglietto, Catriona Maclean, Ken Offit, Mark Robson, Vijai Joseph, Mia Gaudet, Esther M John, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene Andrulis, Julia A Knight, Anna Marie Mulligan, Frances P O'Malley, Louise A Brinton, Mark E Sherman, Jolanta Lissowska, Stephen J Chanock, Maartje Hooning, John W M Martens, Ans M W van den Ouweland, J Margriet Collée, Per Hall, Kamila Czene, Angela Cox, Ian W Brock, Malcolm W R Reed, Simon S Cross, Paul Pharoah, Alison M Dunning, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Sei-Hyun Ahn, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska, Katarzyna Durda, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Chen-Yang Shen, Shian-Ling Ding, Huan-Ming Hsu, Jyh-Cherng Yu, Hoda Anton-Culver, Argyrios Ziogas, Alan Ashworth, Anthony Swerdlow, Michael Jones, Nick Orr, Amy Trentham-Dietz, Kathleen Egan, Polly Newcomb, Linda Titus-Ernstoff, Doug Easton, Amanda B Spurdle.
Hum. Mol. Genet.
PUBLISHED: 08-18-2011
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A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2)= 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heterogeneity = 7.6 × 10(-5)]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P= 6.7 × 10(-3)) and lobular histology (case-only P= 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.
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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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The potential value of sibling controls compared with population controls for association studies of lifestyle-related risk factors: an example from the Breast Cancer Family Registry.
Int J Epidemiol
PUBLISHED: 07-19-2011
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A previous Australian population-based breast cancer case-control study found indirect evidence that control participation, although high, was not random. We hypothesized that unaffected sisters may provide a more appropriate comparison group than unrelated population controls.
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Adherence to breast and ovarian cancer screening recommendations for female relatives from the Ontario site of the Breast Cancer Family Registry.
Eur. J. Cancer Prev.
PUBLISHED: 06-22-2011
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This study compares adherence to breast and ovarian cancer screening recommendations among a population cohort of women at familial risk of breast and/or ovarian cancer. This cross-sectional study included 1039 first-degree female relatives without breast cancer identified from the Ontario site of the Breast Cancer Family Registry. We compared breast and ovarian cancer screening behaviors, using a telephone-administered questionnaire among three groups of women defined by their familial risk (high, moderate, and low) of breast and/or ovarian cancer. Associations between screening behaviors and familial risk were assessed using multinomial regression models adjusted by familial clustering. Women, 40-49 years of age, at moderate or high familial risk were significantly more likely to have had a screening mammogram within the past 12 months [odds ratio (OR): 2.80; 95% confidence interval (CI): 1.40-5.58], and women of less than 50 years of age were more likely to have a clinical breast examination (OR: 1.84; 95% CI: 1.02-3.31) compared with women at low familial risk. Compared with women at low or moderate familial risk, women at high familial risk were significantly more likely to have ever had a genetic test for the BRCA 1/2 genes (OR: 2.67; 95% CI: 1.76-4.05). Although the overall level of adherence among high-risk women is suboptimal in the community, women at a higher familial risk are adhering more often to cancer screening recommendations than women at a lower familial risk.
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Vitamin D-related genetic variants, interactions with vitamin D exposure, and breast cancer risk among Caucasian women in Ontario.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 06-21-2011
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Vitamin D, from diet and sunlight exposure, may be associated with reduced breast-cancer risk. This study investigated if candidate gene variants in vitamin D pathways are associated with breast cancer risk, or modify the associations between breast cancer and vitamin D exposure.
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Ultraviolet sunlight exposure during adolescence and adulthood and breast cancer risk: a population-based case-control study among Ontario women.
Am. J. Epidemiol.
PUBLISHED: 06-09-2011
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Recent studies suggest that vitamin D may be associated with reduced breast cancer risk, but most studies have evaluated only dietary vitamin D intake. The associations among ultraviolet radiation from sunlight, factors related to cutaneous vitamin D production, and breast cancer risk were evaluated in a population-based case-control study conducted in Ontario, Canada, between 2003 and 2004 (n = 3,101 cases and n = 3,471 controls). Time spent outdoors was associated with reduced breast cancer risk during 4 periods of life (>21 vs. ?6 hours/week age-adjusted odds ratio (OR) = 0.71, 95% confidence interval (CI): 0.60, 0.85 in the teenage years; OR = 0.64, 95% CI: 0.53, 0.76 in the 20s-30s; OR = 0.74, 95% CI: 0.61, 0.88 in the 40s-50s; and OR = 0.50, 95% CI: 0.37, 0.66 in the 60s-74 years). Sun protection practices and ultraviolet radiation were not associated with breast cancer risk. A combined solar vitamin D score, including all the variables related to vitamin D production, was significantly associated with reduced breast cancer risk. These associations were not confounded or modified by menopausal status, dietary vitamin D intake, or physical activity. This study suggests that factors suggestive of increased cutaneous production of vitamin D are associated with reduced breast cancer risk.
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Influence of perceived breast cancer risk on screening behaviors of female relatives from the Ontario site of the Breast Cancer Family Registry.
Eur. J. Cancer Prev.
PUBLISHED: 04-07-2011
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Few studies have examined the influence of perceived risk on breast screening behaviors among women with an increased familial breast cancer risk. This study included 1019 women aged 20-71 years from the Ontario site of the Breast Cancer Family Registry who had at least one first-degree relative diagnosed with breast and/or ovarian cancer. Information was obtained from a self-administered questionnaire completed at the time of recruitment and a follow-up telephone questionnaire. The associations between breast screening behaviors and perceived risk of developing breast cancer, measured on both a numerical and Likert-type verbal scale, were estimated using logistic regression analyses. Women who rated their risk of developing breast cancer as greater than 50% compared with less than 50% were significantly more likely to have a screening mammogram within the last 12 months (odds ratio: 1.91; 95% confidence interval: 1.15-3.16). Women were significantly more likely to have a screening mammogram (odds ratio: 1.82; 95% confidence interval: 1.17-2.81) in the past 12 months if they rated their risk as above or much above average compared with same as average or below. These findings may inform educational messages for improving risk communication of women at elevated familial breast cancer risk.
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Interferon ?-1b directly modulates human neural stem/progenitor cell fate.
Brain Res.
PUBLISHED: 03-17-2011
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Interferon beta (IFN-?) is a mainline treatment for multiple sclerosis (MS); however its exact mechanism of action is not completely understood. IFN-? is known as an immunomodulator; although recent evidence suggests that IFN-? may also act directly on neural stem/progenitor cells (NPCs) in the central nervous system (CNS). NPCs can differentiate into all neural lineage cells, which could contribute to the remyelination and repair of MS lesions. Understanding how IFN-? influences NPC physiology is critical to develop more specific therapies that can better assist this repair process. In this study, we investigated the effects of IFN ?-1b (Betaseron®) on human NPCs in vitro (hNPCs). Our data demonstrate a dose-dependent response of hNPCs to IFN ?-1b treatment via sustained proliferation and differentiation. Furthermore, we offer insight into the signaling pathways involved in these mechanisms. Overall, this study shows a direct effect of IFN ?-1b on hNPCs and highlights the need to further understand how current MS treatments can modulate endogenous NPC populations within the CNS.
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Promoter methylation of Wnt antagonists DKK1 and SFRP1 is associated with opposing tumor subtypes in two large populations of colorectal cancer patients.
Carcinogenesis
PUBLISHED: 02-08-2011
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Aberrant activation of canonical Wnt signaling is a hallmark event in colorectal carcinogenesis. The Dickkopf-1 (DKK1) and Secreted Frizzled Related Protein 1 (SFRP1) genes encode extracellular inhibitors of Wnt signaling that are frequently silenced by promoter hypermethylation in colorectal cancer (CRC). These methylation events have been identified as prognostic markers of patient outcome and tumor subtype in several cancers but similar roles in CRC have not been comprehensively examined. In CRC, the microsatellite instability (MSI) subtype associates with favorable disease outcome but the molecular events that are responsible remain poorly understood. Consequently, we quantified promoter methylation status of the Wnt antagonist genes DKK1 and SFRP1 in a large population-based cohort of CRCs from Ontario (n = 549) and Newfoundland (n = 696) stratified by MSI status. We examined the association between methylation status and clinicopathological features including tumor MSI status and patient survival. DKK1 and SFRP1 were methylated in 13 and 95% of CRCs, respectively. In Ontario, DKK1 methylation was strongly associated with MSI tumors after adjustment for age, sex and tumor location [odds ratio (OR) = 13.7, 95% confidence interval (CI) = 7.8-24.2, P < 0.001]. Conversely, SFRP1 methylation was inversely associated with MSI tumors after these adjustments (OR = 0.3, 95% CI = 0.1-0.9, P = 0.009). Similar results were obtained in Newfoundland. There were no independent associations with recurrence-free survival. This is the first large study to identify associations between Wnt antagonist promoter hypermethylation and CRC MSI subtype. These events provide insight into subtype-specific epigenetic mediation of Wnt signaling in CRC.
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Identification of germline alterations of the mad homology 2 domain of SMAD3 and SMAD4 from the Ontario site of the breast cancer family registry (CFR).
Breast Cancer Res.
PUBLISHED: 02-03-2011
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A common feature of neoplastic cells is that mutations in SMADs can contribute to the loss of sensitivity to the anti-tumor effects of transforming growth factor-? (TGF-?). However, germline mutation analysis of SMAD3 and SMAD4, the principle substrates of the TGF-? signaling pathway, has not yet been conducted in breast cancer. Thus, it is currently unknown whether germline SMAD3 and SMAD4 mutations are involved in breast cancer predisposition.
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Cross-talk between CD4+ T-cells and neural stem/progenitor cells.
J. Neurol. Sci.
PUBLISHED: 01-25-2011
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Immune-neural interactions dictate both lesion formation and repair in multiple sclerosis (MS). MS pathogenesis is mediated by the interplay of invading immune cells, neurons, glia, and endogenous stores of neural stem/progenitor cells (NPCs). However, the signals important in this cross-talk are not well defined. We utilized a co-culture method and flow cytometric analysis capable of detecting outcomes for both cell types. Here we describe the effects of NPCs on three different CD4+ subtypes (Th1, Th2, and Th17) and vice versa. Utilizing lpr (Fas receptor-deficient) and gld (Fas ligand-deficient) NPC lines, we further define the role of Fas in this neuroimmune cross-talk. We show that only the Th1 subtype is capable of inducing NPC cell death, and this is independent of Fas activation. Conversely, NPCs specifically kill pro-inflammatory Th1 and Th17 cells in a contact-dependent manner without affecting Th2 survival. Further investigation into these effects revealed that FasL expressed by NPCs mediates Th17 apoptosis. Additionally NPC/T-cell cross-talk modulates FasL expression in both cell types, while Fas receptor levels remains static. These findings illuminate the direct neuropathogenic effects of T-cells, as well as help define the immunomodulatory capacity of NPCs. We have elucidated novel interactions that may be critical in MS pathogenesis.
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Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies.
Xiaohong R Yang, Jenny Chang-Claude, Ellen L Goode, Fergus J Couch, Heli Nevanlinna, Roger L Milne, Mia Gaudet, Marjanka K Schmidt, Annegien Broeks, Angela Cox, Peter A Fasching, Rebecca Hein, Amanda B Spurdle, Fiona Blows, Kristy Driver, Dieter Flesch-Janys, Judith Heinz, Peter Sinn, Alina Vrieling, Tuomas Heikkinen, Kristiina Aittomäki, Päivi Heikkilä, Carl Blomqvist, Jolanta Lissowska, Beata Peplonska, Stephen Chanock, Jonine Figueroa, Louise Brinton, Per Hall, Kamila Czene, Keith Humphreys, Hatef Darabi, Jianjun Liu, Laura J van 't Veer, Flora E van Leeuwen, Irene L Andrulis, Gord Glendon, Julia A Knight, Anna Marie Mulligan, Frances P O'Malley, Nayana Weerasooriya, Esther M John, Matthias W Beckmann, Arndt Hartmann, Sebastian B Weihbrecht, David L Wachter, Sebastian M Jud, Christian R Loehberg, Laura Baglietto, Dallas R English, Graham G Giles, Catriona A McLean, Gianluca Severi, Diether Lambrechts, Thijs Vandorpe, Caroline Weltens, Robert Paridaens, Ann Smeets, Patrick Neven, Hans Wildiers, Xianshu Wang, Janet E Olson, Victoria Cafourek, Zachary Fredericksen, Matthew Kosel, Celine Vachon, Helen E Cramp, Daniel Connley, Simon S Cross, Sabapathy P Balasubramanian, Malcolm W R Reed, Thilo Dörk, Michael Bremer, Andreas Meyer, Johann H Karstens, Aysun Ay, Tjoung-Won Park-Simon, Peter Hillemanns, José Ignacio Arias Perez, Primitiva Menéndez Rodríguez, Pilar Zamora, Javier Benitez, Yon-Dschun Ko, Hans-Peter Fischer, Ute Hamann, Beate Pesch, Thomas Brüning, Christina Justenhoven, Hiltrud Brauch, Diana M Eccles, William J Tapper, Sue M Gerty, Elinor J Sawyer, Ian P Tomlinson, Angela Jones, Michael Kerin, Nicola Miller, Niall McInerney, Hoda Anton-Culver, Argyrios Ziogas, Chen-Yang Shen, Chia-Ni Hsiung, Pei-Ei Wu, Show-Lin Yang, Jyh-Cherng Yu, Shou-Tung Chen, Giu-Cheng Hsu, Christopher A Haiman, Brian E Henderson, Loic Le Marchand, Laurence N Kolonel, Annika Lindblom, Sara Margolin, Anna Jakubowska, Jan Lubiński, Tomasz Huzarski, Tomasz Byrski, Bohdan Górski, Jacek Gronwald, Maartje J Hooning, Antoinette Hollestelle, Ans M W van den Ouweland, Agnes Jager, Mieke Kriege, Madeleine M A Tilanus-Linthorst, Margriet Collée, Shan Wang-Gohrke, Katri Pylkäs, Arja Jukkola-Vuorinen, Kari Mononen, Mervi Grip, Pasi Hirvikoski, Robert Winqvist, Arto Mannermaa, Veli-Matti Kosma, Jaana Kauppinen, Vesa Kataja, Päivi Auvinen, Ylermi Soini, Reijo Sironen, Stig E Bojesen, David Dynnes Ørsted, Diljit Kaur-Knudsen, Henrik Flyger, Børge G Nordestgaard, Helene Holland, Georgia Chenevix-Trench, Siranoush Manoukian, Monica Barile, Paolo Radice, Susan E Hankinson, David J Hunter, Rulla Tamimi, Suleeporn Sangrajrang, Paul Brennan, James McKay, Fabrice Odefrey, Valerie Gaborieau, Peter Devilee, P E A Huijts, R A E M Tollenaar, C Seynaeve, Gillian S Dite, Carmel Apicella, John L Hopper, Fleur Hammet, Helen Tsimiklis, Letitia D Smith, Melissa C Southey, Manjeet K Humphreys, Douglas Easton, Paul Pharoah, Mark E Sherman, Montserrat Garcia-Closas.
J. Natl. Cancer Inst.
PUBLISHED: 12-29-2010
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Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.
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Vitamin D intake from food and supplements among Ontario women based on the US block food frequency questionnaire with and without modification for Canadian food values.
Can J Public Health
PUBLISHED: 11-02-2010
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To measure and compare dietary vitamin D intake among women in Ontario using a modified Block 1998 (US) food frequency questionnaire (FFQ) before and after modification for Canadian-specific vitamin D food fortification.
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Association of 25(OH)D and PTH with metabolic syndrome and its traditional and nontraditional components.
J. Clin. Endocrinol. Metab.
PUBLISHED: 10-27-2010
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Emerging evidence suggests that 25-hydroxy vitamin D [25(OH)D] and PTH may play a role in the etiology of the metabolic syndrome (MetS). However, evidence to date is limited and inconsistent, and few studies have examined associations with nontraditional MetS components.
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Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study.
Breast Cancer Res.
PUBLISHED: 08-25-2010
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Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium.
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Vitamin D and calcium intakes and breast cancer risk in pre- and postmenopausal women.
Am. J. Clin. Nutr.
PUBLISHED: 04-14-2010
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Some evidence suggests that vitamin D may reduce breast cancer risk. Despite the biological interaction between vitamin D and calcium, few studies have evaluated their joint effects on breast cancer risk.
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Family-based association study of IGF1 microsatellites and height, weight, and body mass index.
J. Hum. Genet.
PUBLISHED: 03-19-2010
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Height, weight, and body mass index (BMI) are partly heritable, known to be associated with chronic diseases, and are linked to circulating insulin-like growth factor I (IGF-I) concentrations. IGF-I concentrations are also partly heritable and thus genetic variation at IGF1 could influence height, weight, BMI and the risk of developing chronic diseases. Our objective was to examine the association of genetic variation at IGF1 with height, weight and BMI using a sample of premenopausal women. A family-based study design was used to investigate the association of three IGF1 CA repeat variants at 5 (5CA), intron 2 (In2CA) and 3 (3CA) with these anthropometric measures. We analyzed the data for 827 families of different sizes and configurations, which included 1520 premenopausal women. Nominally significant associations (P
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Optical spectroscopy of the breast in premenopausal women reveals tissue variation with changes in age and parity.
Med Phys
PUBLISHED: 03-17-2010
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Variations during breast tissue development can influence later breast cancer risk. In particular, prolonged nulliparity increases risk. The authors used optical spectroscopy to compare breast tissue in 115 nulliparous women aged 31-40 (group 2) to 140 nulliparous women aged 18-21 (group 1), and also to 36 parous women aged 31-40 (group 3), and to evaluate the relationship between IGF-1 and optical breast tissue properties. IGF-1 has been linked in particular to premenopausal breast cancer.
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Association of vitamin D with insulin resistance and beta-cell dysfunction in subjects at risk for type 2 diabetes.
Diabetes Care
PUBLISHED: 03-09-2010
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To examine cross-sectional associations of serum vitamin D [25-hydroxyvitamin D, 25(OH)D] concentration with insulin resistance (IR) and beta-cell dysfunction in 712 subjects at risk for type 2 diabetes.
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Association between IGF1 CA microsatellites and mammographic density, anthropometric measures, and circulating IGF-I levels in premenopausal Caucasian women.
Breast Cancer Res. Treat.
PUBLISHED: 09-09-2009
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Results from several studies indicate that mammographic density, a strong risk factor for breast cancer, is greater in premenopausal women with higher circulating IGF-I levels. Both mammographic density and circulating IGF-I levels appear to be partly heritable traits. We hypothesized that in premenopausal women, IGF1 variants are associated with circulating IGF-I concentration, which in turn influences variation in breast density. Therefore, we examined the association of IGF1 polymorphisms with circulating IGF-I levels and mammographic density.
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The effect of interferon-beta on mouse neural progenitor cell survival and differentiation.
Biochem. Biophys. Res. Commun.
PUBLISHED: 07-10-2009
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Interferon-beta (IFN-beta) is a mainstay therapy for relapse-remitting multiple sclerosis (MS). However, the direct effects of IFN-beta on the central nervous system (CNS) are not well understood. To determine whether IFN-beta has direct neuroprotective effects on CNS cells, we treated adult mouse neural progenitor cells (NPCs) in vitro with IFN-beta and examined the effects on proliferation, apoptosis, and differentiation. We found that mouse NPCs express high levels of IFNalpha/beta receptor (IFNAR). In response to IFN-beta treatment, no effect was observed on differentiation or proliferation. However, IFN-beta treated mouse NPCs demonstrated decreased apoptosis upon growth factor withdrawal. Pathway-specific polymerase chain reaction (PCR) arrays demonstrated that IFN-beta treatment upregulated the STAT 1 and 2 signaling pathway, as well as GFRA2, NOD1, Caspases 1 and 12, and TNFSF10. These results suggest that IFN-beta can directly affect NPC survival, possibly playing a neuroprotective role in the CNS by modulating neurotrophic factors.
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Family history of hormonal cancers and colorectal cancer risk: a case-control study conducted in Ontario.
Int. J. Cancer
PUBLISHED: 05-14-2009
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Aggregation of cancers among families with highly penetrant genetic mutations such as hereditary nonpolyposis colorectal cancer is well-described. However, there is a paucity of data regarding familial aggregation of hormonal cancers (cancers of the breast, endometrial, ovarian and prostate) and colorectal cancer (CRC) in the general population. We investigated the association between having a first-degree family history of breast, endometrial, ovarian, or prostate cancer and CRC risk. Population-based CRC cases and controls were recruited by the Ontario Familial Colorectal Cancer Registry (OFCCR). Logistic regression was conducted to obtain odds ratio (OR) estimates and 95% confidence intervals (95% CIs). First-degree family history of breast cancer was associated with a modest, borderline statistically significant increased CRC risk (age-, sex-adjusted OR = 1.2, 95% CI = 1.0, 1.5). The magnitude of CRC risk was greatest if more than one first-degree kin had breast cancer (age-, sex-adjusted OR = 1.7, 95% CI = 1.0, 2.0), as well as if the kin was diagnosed at >50 years of age (age-, sex-adjusted OR = 1.4, 95% CI = 1.1, 1.8). Family history of ovarian cancer was associated with reduced CRC risk (multivariate-adjusted OR = 0.6, 95% CI = 0.3, 1.0). Although statistically significant increases in CRC risk were observed in the age-, sex-adjusted OR estimates for family history of endometrial and prostate cancers, the associations were no longer significant after multivariate-adjustment. In conclusion, individuals with a first-degree kin with breast cancer may have a modest increased risk for CRC compared to individuals without.
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Alcohol intake and cigarette smoking and risk of a contralateral breast cancer: The Womens Environmental Cancer and Radiation Epidemiology Study.
Am. J. Epidemiol.
PUBLISHED: 02-11-2009
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Women with primary breast cancer are at increased risk of developing second primary breast cancer. Few studies have evaluated risk factors for the development of asynchronous contralateral breast cancer in women with breast cancer. In the Womens Environmental Cancer and Radiation Epidemiology Study (1985-2001), the roles of alcohol and smoking were examined in 708 women with asynchronous contralateral breast cancer (cases) compared with 1,399 women with unilateral breast cancer (controls). Cases and controls aged less than 55 years at first breast cancer diagnosis were identified from 5 population-based cancer registries in the United States and Denmark. Controls were matched to cases on birth year, diagnosis year, registry region, and race and countermatched on radiation treatment. Risk factor information was collected by telephone interview. Rate ratios and 95% confidence intervals were estimated by using conditional logistic regression. Ever regular drinking was associated with an increased risk of asynchronous contralateral breast cancer (rate ratio = 1.3, 95% confidence interval: 1.0, 1.6), and the risk increased with increasing duration (P = 0.03). Smoking was not related to asynchronous contralateral breast cancer. In this, the largest study of asynchronous contralateral breast cancer to date, alcohol is a risk factor for the disease, as it is for a first primary breast cancer.
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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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Family-based genetic association study of insulin-like growth factor I microsatellite markers and premenopausal breast cancer risk.
Breast Cancer Res. Treat.
PUBLISHED: 01-31-2009
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Several studies suggest that higher circulating insulin-like growth factor I (IGF-I) levels are associated with premenopausal breast cancer risk. Breast cancer risk and circulating IGF-I concentration appear to be partly heritable, thus genetic variation at IGF1 could influence IGF-I levels and breast cancer risk. We investigated the association of IGF1 CA repeat variants with premenopausal breast cancer risk using a family-based design. The study sample included 840 families from the Ontario Familial Breast Cancer Registry (OFBCR) and the Australian Breast Cancer Family Registry (ABCFR). Three CA repeat variants, at 5, 3, and in intron 2 were genotyped (5CA, 3CA, In2CA). We found several nominally significant associations. The 5CA-21 allele (P = 0.03) and In2CA-212 allele (P = 0.04) were associated with lower risk, and the In2CA-216 allele with higher risk (P = 0.04) for the combined ABCFR-OFBCR. These associations were not significant after taking into account multiple comparisons. In2CA-216 was more strongly associated with risk when we used a recessive instead of an additive model (P = 0.01). 5CA alleles of repeat length 18-20 were associated with higher risk (P = 0.02), and 5CA alleles of >20 repeats were associated with lower risk (P = 0.01). These associations were significant in the OFBCR (In2CA-216 recessive, P = 0.02; 5CA 18-20 and >20 allele grouping, P = 0.01) but not strongly supported by the ABCFR (In2CA-216 recessive, P = 0.14; 5CA 18-20, P = 0.25; 5CA >20, P = 0.20). The associations we found could be due to chance as many comparisons were made. Our results do not strongly support an association between these IGF1 variants and breast cancer risk.
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Accuracy of Self-Reported Breast Cancer Information among Women from the Ontario Site of the Breast Cancer Family Registry.
J Cancer Epidemiol
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Obtaining complete medical record information can be challenging and expensive in breast cancer studies. The current literature is limited with respect to the accuracy of self-report and factors that may influence this. We assessed the agreement between self-reported and medical record breast cancer information among women from the Ontario site of the Breast Cancer Family Registry. Women aged 20-69 years diagnosed with incident breast cancer 1996-1998 were identified from the Ontario Cancer Registry, sampled on age and family history. We calculated kappa statistics, proportion correct, sensitivity, specificity, and positive and negative predictive values and conducted unconditional logistic regression to examine whether characteristics of the women influenced agreement. The proportions of women who correctly reported having received a broad category of therapy (hormone therapy, chemotherapy, radiation, or surgery) as well as sensitivity and specificity were above 90%, and the kappa statistics were above 0.80. The specific type of hormonal or chemotherapy was reported with low-to-moderate agreement. Aside from recurrence, no factors were consistently associated with agreement. Thus, most women were able to accurately report broad categories of treatment but not necessarily specific treatment types. The finding of this study can aid researchers in the use and design of self-administered treatment questionnaires.
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Total energy intake and breast cancer risk in sisters: the Breast Cancer Family Registry.
Breast Cancer Res. Treat.
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Energy restriction inhibits mammary tumor development in animal models. Epidemiologic studies in humans generally do not support an association between dietary energy intake and breast cancer risk, although some studies suggest a more complex interplay between measures of energy intake, physical activity, and body size. We examined the association between total energy intake jointly with physical activity and body mass index (BMI) and the risk of breast cancer among 1,775 women diagnosed with breast cancer between 1995 and 2006 and 2,529 of their unaffected sisters, enrolled in the Breast Cancer Family Registry. We collected dietary data using the Hawaii-Los Angeles Multiethnic Cohort food frequency questionnaire. Using conditional logistic regression to estimate the odds ratios (OR) and 95 % confidence intervals (CI) associated with total energy intake, we observed an overall 60-70 % increased risk of breast cancer among women in the highest quartile of total energy intake compared to those in the lowest quartile (Q4 vs. Q1: OR = 1.6, 95 % CI: 1.3-2.0; P (trend) < 0.0001); these associations were limited to pre-menopausal women or women with hormone receptor-positive cancers. Although the associations were slightly stronger among women with a higher BMI or lower level of average lifetime physical activity, we observed a positive association between total energy intake and breast cancer risk across different strata of physical activity and BMI. Our results suggest that within sisters, high energy intake may increase the risk of breast cancer independent of physical activity and body size. If replicated in prospective studies, then these findings suggest that reductions in total energy intake may help in modifying breast cancer risk.
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CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer.
J. Clin. Oncol.
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We tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer-specific death, and risk of a second breast cancer in women with a first breast cancer.
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Variation in genes related to obesity, weight, and weight change and risk of contralateral breast cancer in the WECARE Study population.
Cancer Epidemiol. Biomarkers Prev.
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Body mass index (BMI), a known breast cancer risk factor, could influence breast risk through mechanistic pathways related to sex hormones, insulin resistance, chronic inflammation, and altered levels of adipose-derived hormones. Results from studies of the relationship between BMI and second primary breast cancer have been mixed. To explore the relationship between BMI and asynchronous contralateral breast cancer (CBC), we examined whether variants in genes related to obesity, weight, and weight change are associated with CBC risk.
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Vitamin D intake is negatively associated with promoter methylation of the Wnt antagonist gene DKK1 in a large group of colorectal cancer patients.
Nutr Cancer
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Diet and lifestyle influence colorectal cancer (CRC) risk but the molecular events that mediate these effects are poorly characterized. Several dietary and lifestyle factors can modulate DNA methylation suggesting that they may influence CRC risk through epigenetic regulation of cancer-related genes. The Wnt regulatory genes DKK1 and Wnt5a are important contributors to colonic carcinogenesis and are often silenced by promoter hypermethylation in CRC; however, the dietary contributions to these events have not been explored. To investigate the link between dietary/lifestyle factors and epigenetic regulation of these Wnt signaling genes, we assessed promoter methylation of these genes in a large cohort of Canadian CRC patients from Ontario (n = 549) and Newfoundland (n = 443) and examined associations to dietary/lifestyle factors implicated in CRC risk and/or DNA methylation including intake of vitamins, fats, cholesterol, fiber, and alcohol as well as body mass index (BMI), and smoking status. Several factors were associated with methylation status including alcohol intake, BMI, and cigarette smoking. Most significantly, however, dietary vitamin D intake was strongly negatively associated with DKK1 methylation in Newfoundland (P = 0.001) and a similar trend was observed in Ontario. These results suggest that vitamin D and other dietary/lifestyle factors may alter CRC risk by mediating extracellular Wnt inhibition.
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Solar ultraviolet-B radiation and vitamin D: a cross-sectional population-based study using data from the 2007 to 2009 Canadian Health Measures Survey.
BMC Public Health
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Exposure to solar ultraviolet-B (UV-B) radiation is a major source of vitamin D3. Chemistry climate models project decreases in ground-level solar erythemal UV over the current century. It is unclear what impact this will have on vitamin D status at the population level. The purpose of this study was to measure the association between ground-level solar UV-B and serum concentrations of 25-hydroxyvitamin D (25(OH)D) using a secondary analysis of the 2007 to 2009 Canadian Health Measures Survey (CHMS).
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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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Worry is good for breast cancer screening: a study of female relatives from the ontario site of the breast cancer family registry.
J Cancer Epidemiol
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Background. Few prospective studies have examined associations between breast cancer worry and screening behaviours in women with elevated breast cancer risks based on family history. Methods. This study included 901 high familial risk women, aged 23-71 years, from the Ontario site of the Breast Cancer Family Registry. Self-reported breast screening behaviours at year-one followup were compared between women at low (N = 305), medium (N = 433), and high (N = 163) levels of baseline breast cancer worry using logistic regression. Nonlinear relationships were assessed using likelihood ratio tests. Results. A significant non-linear inverted "U" relationship was observed between breast cancer worry and mammography screening (P = 0.034) for all women, where women at either low or high worry levels were less likely than those at medium to have a screening mammogram. A similar significant non-linear inverted "U" relationship was also found among all women and women at low familial risk for worry and screening clinical breast examinations (CBEs). Conclusions. Medium levels of cancer worries predicted higher rates of screening mammography and CBE among high-risk women.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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