JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
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
Show Abstract
Hide Abstract
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.
Related JoVE Video
Playing with opening and closing of heterocycles: using the cusmano-ruccia reaction to develop a novel class of oxadiazolothiazinones, active as calcium channel modulators and p-glycoprotein inhibitors.
Molecules
PUBLISHED: 06-20-2014
Show Abstract
Hide Abstract
As a result of the ring-into-ring conversion of nitrosoimidazole derivatives, we obtained a molecular scaffold that, when properly decorated, is able to decrease inotropy by blocking L-type calcium channels. Previously, we used this scaffold to develop a quantitative structure-activity relationship (QSAR) model, and we used the most potent oxadiazolothiazinone as a template for ligand-based virtual screening. Here, we enlarge the diversity of chemical decorations, present the synthesis and in vitro data for 11 new derivatives, and develop a new 3D-QSAR model with recent in silico techniques. We observed a key role played by the oxadiazolone moiety: given the presence of positively charged calcium ions in the transmembrane channel protein, we hypothesize the formation of a ternary complex between the oxadiazolothiazinone, the Ca2+ ion and the protein. We have supported this hypothesis by means of pharmacophore generation and through the docking of the pharmacophore into a homology model of the protein. We also studied with docking experiments the interaction with a homology model of P-glycoprotein, which is inhibited by this series of molecules, and provided further evidence toward the relevance of this scaffold in biological interactions.
Related JoVE Video
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
Show Abstract
Hide Abstract
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.
Related JoVE Video
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
Show Abstract
Hide Abstract
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.
Related JoVE Video
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
Show Abstract
Hide Abstract
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.
Related JoVE Video
Investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors.
Int. J. Cancer
PUBLISHED: 04-03-2014
Show Abstract
Hide Abstract
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.
Related JoVE Video
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
Show Abstract
Hide Abstract
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.
Related JoVE Video
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
Show Abstract
Hide Abstract
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.
Related JoVE Video
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
Show Abstract
Hide Abstract
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.
Related JoVE Video
Different molecular profiles are associated with breast cancer cell homing compared with colonisation of bone: evidence using a novel bone-seeking cell line.
Endocr. Relat. Cancer
PUBLISHED: 01-01-2014
Show Abstract
Hide Abstract
Advanced breast cancer is associated with the development of incurable bone metastasis. The two key processes involved, tumour cell homing to and subsequent colonisation of bone, remain to be clearly defined. Genetic studies have indicated that different genes facilitate homing and colonisation of secondary sites. To identify specific changes in gene and protein expression associated with bone-homing or colonisation, we have developed a novel bone-seeking clone of MDA-MB-231 breast cancer cells that exclusively forms tumours in long bones following i.v. injection in nude mice. Bone-homing cells were indistinguishable from parental cells in terms of growth rate in vitro and when grown subcutaneously in vivo. Only bone-homing ability differed between the lines; once established in bone, tumours from both lines displayed similar rates of progression and caused the same extent of lytic bone disease. By comparing the molecular profile of a panel of metastasis-associated genes, we have identified differential expression profiles associated with bone-homing or colonisation. Bone-homing cells had decreased expression of the cell adhesion molecule fibronectin and the migration and calcium signal binding protein S100A4, in addition to increased expression of interleukin 1B. Bone colonisation was associated with increased fibronectin and upregulation of molecules influencing signal transduction pathways and breakdown of extracellular matrix, including hRAS and matrix metalloproteinase 9. Our data support the hypothesis that during early stages of breast cancer bone metastasis, a specific set of genes are altered to facilitate bone-homing, and that disruption of these may be required for effective therapeutic targeting of this process.
Related JoVE Video
Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple negative breast cancer.
Kristen S Purrington, Susan Slager, Diana Eccles, Drakoulis Yannoukakos, Peter A Fasching, Penelope Miron, Jane Carpenter, Jenny Chang-Claude, Nicholas G Martin, Grant W Montgomery, Vessela Kristensen, Hoda Anton-Culver, Paul Goodfellow, William J Tapper, Sajjad Rafiq, Susan M Gerty, Lorraine Durcan, Irene Konstantopoulou, Florentia Fostira, Athanassios Vratimos, Paraskevi Apostolou, Irene Konstanta, Vassiliki Kotoula, Sotiris Lakis, Meletios A Dimopoulos, Dimosthenis Skarlos, Dimitrios Pectasides, George Fountzilas, Matthias W Beckmann, Alexander Hein, Matthias Ruebner, Arif B Ekici, Arndt Hartmann, Ruediger Schulz-Wendtland, Stefan P Renner, Wolfgang Janni, Brigitte Rack, Christoph Scholz, Julia Neugebauer, Ulrich Andergassen, Michael P Lux, Lothar Haeberle, Christine Clarke, Nirmala Pathmanathan, Anja Rudolph, Dieter Flesch-Janys, Stefan Nickels, Janet E Olson, James N Ingle, Curtis Olswold, Seth Slettedahl, Jeanette E Eckel-Passow, S Keith Anderson, Daniel W Visscher, Victoria L Cafourek, Hugues Sicotte, Naresh Prodduturi, Elisabete Weiderpass, Leslie Bernstein, Argyrios Ziogas, Jennifer Ivanovich, Graham G Giles, Laura Baglietto, Melissa Southey, Veli-Matti Kosma, Hans-Peter Fischer, , Malcom W R Reed, Simon S Cross, Sandra Deming-Halverson, Martha Shrubsole, Qiuyin Cai, Xiao-Ou Shu, Mary Daly, Joellen Weaver, Eric Ross, Jennifer Klemp, Priyanka Sharma, Diana Torres, Thomas Rüdiger, Heidrun Wölfing, Hans-Ulrich Ulmer, Asta Försti, Thaer Khoury, Shicha Kumar, Robert Pilarski, Charles L Shapiro, Dario Greco, Päivi Heikkilä, Kristiina Aittomäki, Carl Blomqvist, Astrid Irwanto, Jianjun Liu, Vernon Shane Pankratz, Xianshu Wang, Gianluca Severi, Arto Mannermaa, Douglas Easton, Per Hall, Hiltrud Brauch, Angela Cox, Wei Zheng, Andrew K Godwin, Ute Hamann, Christine Ambrosone, Amanda Ewart Toland, Heli Nevanlinna, Celine M Vachon, Fergus J Couch.
Carcinogenesis
PUBLISHED: 12-09-2013
Show Abstract
Hide Abstract
Triple negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study (GWAS) of TN breast cancer (stage 1: 1,529 TN cases, 3,399 controls; stage 2: 2,148 cases, 1,309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (p<5x10(-8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the SNPs analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (p<0.05). Associations with TN breast cancer were confirmed for ten loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (p<0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 (rs12525163 Odds Ratio (OR)=1.15, p=4.9x10(-4)) and 19p13.1 (rs1864112 OR=0.84, p=1.8x10(-9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR=4.03, 95% CI 3.46-4.70, p=4.8x10(-69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
Related JoVE Video
Neoadjuvant chemotherapy with or without zoledronic acid in early breast cancer--a randomized biomarker pilot study.
Clin. Cancer Res.
PUBLISHED: 03-20-2013
Show Abstract
Hide Abstract
To investigate the short-term biologic effects of neoadjuvant chemotherapy +/- zoledronic acid (ZOL) in invasive breast cancer.
Related JoVE Video
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
Show Abstract
Hide Abstract
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.
Related JoVE Video
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
Show Abstract
Hide Abstract
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.
Related JoVE Video
Much of the variation in breast pathology quality assurance data in the UK can be explained by the random order in which cases arrive at individual centres, but some true outliers do exist.
Histopathology
PUBLISHED: 09-10-2011
Show Abstract
Hide Abstract
To investigate the role of random temporal order of patient arrival at screening centres in the variability seen in rates of node positivity and breast cancer grade between centres in the NHS Breast Screening Programme.
Related JoVE Video
Expression of class 3 semaphorins and their receptors in human breast neoplasia.
Histopathology
PUBLISHED: 09-03-2011
Show Abstract
Hide Abstract
This study aimed to identify the involvement of class 3 semaphorins (Sema3) and receptors, neuropilins (Np1 and Np2) and plexins (A1-A4) in breast cancer development and angiogenesis.
Related JoVE Video
Angiopoietins 1 and 2 and Tie-2 receptor expression in human ductal breast disease.
Histopathology
PUBLISHED: 09-03-2011
Show Abstract
Hide Abstract
?This study aimed to identify the involvement of the angiopoietin/Tie-2 receptor system in breast cancer development, progression, metastasis and angiogenesis.
Related JoVE Video
Loss of dystroglycan function in oesophageal cancer.
Histopathology
PUBLISHED: 09-03-2011
Show Abstract
Hide Abstract
?Oesophageal cancer is an increasingly common human malignancy, with its incidence in the West rapidly rising. It is associated with a very poor prognosis, and its exact pathogenesis is uncertain. Dystroglycan and E-cadherin are cell adhesion molecules, the loss of which is often related to tumour differentiation, aggressiveness and invasiveness. The aim was therefore to evaluate their roles in oesophageal carcinogenesis.
Related JoVE Video
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
Show Abstract
Hide Abstract
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.
Related JoVE Video
Common breast cancer susceptibility loci are associated with triple-negative breast cancer.
Cancer Res.
PUBLISHED: 08-15-2011
Show Abstract
Hide Abstract
Triple-negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiologic factors that promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome-wide association studies display heterogeneity of effect among breast cancer subtypes as defined by the status of estrogen and progesterone receptors. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple-negative breast cancer and 4,978 healthy controls. We identified six single-nucleotide polymorphisms, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.1), and rs8100241 (19p13.1), significantly associated with the risk of triple-negative breast cancer. Together, our results provide convincing evidence of genetic susceptibility for triple-negative breast cancer.
Related JoVE Video
Combination therapy inhibits development and progression of mammary tumours in immunocompetent mice.
Breast Cancer Res. Treat.
PUBLISHED: 08-02-2011
Show Abstract
Hide Abstract
We have determined the effect of combining the chemotherapy agent doxorubicin and the anti-resorptive drug zoledronic acid on the early stages of spontaneous mammary tumour development using the immunocompetent PyMT mouse model that closely mimics human breast cancer development. 6-week-old PyMT mice were treated weekly for 6 weeks with PBS, 2 mg/kg doxorubicin, 100 ?g/kg zoledronic acid or doxorubicin followed 24 h later by zoledronic acid (n = 15/group). Untreated, 6-week-old animals were used for comparison of tumour development. Tumour volume, apoptosis and angiogenesis were analysed on H&E, caspase 3, CD31 and CD34 stained histological sections. Proliferation was measured by BrdU incorporation and Ki67 staining and tumour macrophage infiltration assessed by F4/80 immunohistochemistry. Animals treated with doxorubicin followed by zoledronic acid did not develop palpable mammary tumours, whereas in all other treatment groups tumours progressed to late stage adenocarcinomas. Tumours from the combination treatment group were of comparable size to those in 6-week-old untreated animals, remaining pre-malignant with well-differentiated acinar arrangements and with tumour volume only reaching on average 26% of that in the PBS control group. Tumour cell apoptosis and proliferation was significantly reduced compared to control, single agent or untreated 6-week-old mice. Significantly fewer circulating tumour cells were present in animals following sequential treatment compared to all other groups. Combination treatment with doxorubicin followed by zoledronic acid inhibits development and progression of spontaneously occurring mammary tumours.
Related JoVE Video
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
Show Abstract
Hide Abstract
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.
Related JoVE Video
A prospective study of duodenal bulb biopsy in newly diagnosed and established adult celiac disease.
Am. J. Gastroenterol.
PUBLISHED: 05-24-2011
Show Abstract
Hide Abstract
Recent reports suggest that the duodenal bulb may be the only site to demonstrate villous atrophy (VA) in celiac disease. However, there is a paucity of data from newly diagnosed adult celiac patients and no data from those patients with established celiac disease. The objective of this study was to compare the histological findings in the duodenal bulb and distal duodenum of patients with adult celiac disease (newly diagnosed or established) against controls.
Related JoVE Video
Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium.
Annegien Broeks, Marjanka K Schmidt, Mark E Sherman, Fergus J Couch, John L Hopper, Gillian S Dite, Carmel Apicella, Letitia D Smith, Fleur Hammet, Melissa C Southey, Laura J van 't Veer, Renate de Groot, Vincent T H B M Smit, Peter A Fasching, Matthias W Beckmann, Sebastian Jud, Arif B Ekici, Arndt Hartmann, Alexander Hein, Ruediger Schulz-Wendtland, Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Hans-Peter Sinn, Christof Sohn, Sandrine Tchatchou, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, David D Ørsted, Diljit Kaur-Knudsen, Roger L Milne, Jose I Arias Pérez, Pilar Zamora, Primitiva Menéndez Rodríguez, Javier Benitez, Hiltrud Brauch, Christina Justenhoven, Yon-Dschun Ko, , Ute Hamann, Hans-Peter Fischer, Thomas Brüning, Beate Pesch, Jenny Chang-Claude, Shan Wang-Gohrke, Michael Bremer, Johann H Karstens, Peter Hillemanns, Thilo Dörk, Heli A Nevanlinna, Tuomas Heikkinen, Päivi Heikkilä, Carl Blomqvist, Kristiina Aittomäki, Kirsimari Aaltonen, Annika Lindblom, Sara Margolin, Arto Mannermaa, Veli-Matti Kosma, Jaana M Kauppinen, Vesa Kataja, Päivi Auvinen, Matti Eskelinen, Ylermi Soini, Georgia Chenevix-Trench, Amanda B Spurdle, Jonathan Beesley, Xiaoqing Chen, Helene Holland, Diether Lambrechts, Bart Claes, Thijs Vandorpe, Patrick Neven, Hans Wildiers, Dieter Flesch-Janys, Rebecca Hein, Thomas Löning, Matthew Kosel, Zachary S Fredericksen, Xianshu Wang, Graham G Giles, Laura Baglietto, Gianluca Severi, Catriona McLean, Christopher A Haiman, Brian E Henderson, Loic Le Marchand, Laurence N Kolonel, Grethe Grenaker Alnæs, Vessela Kristensen, Anne-Lise Børresen-Dale, David J Hunter, Susan E Hankinson, Irene L Andrulis, Anna Marie Mulligan, Frances P O'Malley, Peter Devilee, Petra E A Huijts, Rob A E M Tollenaar, Christi J van Asperen, Caroline S Seynaeve, Stephen J Chanock, Jolanta Lissowska, Louise Brinton, Beata Peplonska, Jonine Figueroa, Xiaohong R Yang, Maartje J Hooning, Antoinette Hollestelle, Rogier A Oldenburg, Agnes Jager, Mieke Kriege, Bahar Ozturk, Geert J L H van Leenders, Per Hall, Kamila Czene, Keith Humphreys, Jianjun Liu, Angela Cox, Daniel Connley, Helen E Cramp, Simon S Cross, Sabapathy P Balasubramanian, Malcolm W R Reed, Alison M Dunning, Douglas F Easton, Manjeet K Humphreys, Carlos Caldas, Fiona Blows, Kristy Driver, Elena Provenzano, Jan Lubiński, Anna Jakubowska, Tomasz Huzarski, Tomasz Byrski, Cezary Cybulski, Bohdan Górski, Jacek Gronwald, Paul Brennan, Suleeporn Sangrajrang, Valerie Gaborieau, Chen-Yang Shen, Chia-Ni Hsiung, Jyh-Cherng Yu, Shou-Tung Chen, Giu-Cheng Hsu, Ming-Feng Hou, Chiun-Sheng Huang, Hoda Anton-Culver, Argyrios Ziogas, Paul D P Pharoah, Montserrat Garcia-Closas.
Hum. Mol. Genet.
PUBLISHED: 05-19-2011
Show Abstract
Hide Abstract
Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 × 10(-18)), rs3803662 (16q12) (P = 3.7 × 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 × 10(-6) and P = 4.1 × 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P ? 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ? 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment.
Related JoVE Video
A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer.
Christopher A Haiman, Gary K Chen, Celine M Vachon, Federico Canzian, Alison Dunning, Robert C Millikan, Xianshu Wang, Foluso Ademuyiwa, Shahana Ahmed, Christine B Ambrosone, Laura Baglietto, Rosemary Balleine, Elisa V Bandera, Matthias W Beckmann, Christine D Berg, Leslie Bernstein, Carl Blomqvist, William J Blot, Hiltrud Brauch, Julie E Buring, Lisa A Carey, Jane E Carpenter, Jenny Chang-Claude, Stephen J Chanock, Daniel I Chasman, Christine L Clarke, Angela Cox, Simon S Cross, Sandra L Deming, Robert B Diasio, Athanasios M Dimopoulos, W Ryan Driver, Thomas Dünnebier, Lorraine Durcan, Diana Eccles, Christopher K Edlund, Arif B Ekici, Peter A Fasching, Heather S Feigelson, Dieter Flesch-Janys, Florentia Fostira, Asta Försti, George Fountzilas, Susan M Gerty, , Graham G Giles, Andrew K Godwin, Paul Goodfellow, Nikki Graham, Dario Greco, Ute Hamann, Susan E Hankinson, Arndt Hartmann, Rebecca Hein, Judith Heinz, Andrea Holbrook, Robert N Hoover, Jennifer J Hu, David J Hunter, Sue A Ingles, Astrid Irwanto, Jennifer Ivanovich, Esther M John, Nicola Johnson, Arja Jukkola-Vuorinen, Rudolf Kaaks, Yon-Dschun Ko, Laurence N Kolonel, Irene Konstantopoulou, Veli-Matti Kosma, Swati Kulkarni, Diether Lambrechts, Adam M Lee, Loic Le Marchand, Timothy Lesnick, Jianjun Liu, Sara Lindstrom, Arto Mannermaa, Sara Margolin, Nicholas G Martin, Penelope Miron, Grant W Montgomery, Heli Nevanlinna, Stephan Nickels, Sarah Nyante, Curtis Olswold, Julie Palmer, Harsh Pathak, Dimitrios Pectasides, Charles M Perou, Julian Peto, Paul D P Pharoah, Loreall C Pooler, Michael F Press, Katri Pylkäs, Timothy R Rebbeck, Jorge L Rodriguez-Gil, Lynn Rosenberg, Eric Ross, Thomas Rüdiger, Isabel dos Santos Silva, Elinor Sawyer, Marjanka K Schmidt, Rüdiger Schulz-Wendtland, Fredrick Schumacher, Gianluca Severi, Xin Sheng, Lisa B Signorello, Hans-Peter Sinn, Kristen N Stevens, Melissa C Southey, William J Tapper, Ian Tomlinson, Frans B L Hogervorst, Els Wauters, Joellen Weaver, Hans Wildiers, Robert Winqvist, David Van Den Berg, Peggy Wan, Lucy Y Xia, Drakoulis Yannoukakos, Wei Zheng, Regina G Ziegler, Afshan Siddiq, Susan L Slager, Daniel O Stram, Douglas Easton, Peter Kraft, Brian E Henderson, Fergus J Couch.
Nat. Genet.
PUBLISHED: 05-03-2011
Show Abstract
Hide Abstract
Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.
Related JoVE Video
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
Show Abstract
Hide Abstract
Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.
Related JoVE Video
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
Show Abstract
Hide Abstract
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.
Related JoVE Video
FLAP: GRID molecular interaction fields in virtual screening. validation using the DUD data set.
J Chem Inf Model
PUBLISHED: 08-10-2010
Show Abstract
Hide Abstract
The performance of FLAP (Fingerprints for Ligands and Proteins) in virtual screening is assessed using a subset of the DUD (Directory of Useful Decoys) benchmarking data set containing 13 targets each with more than 15 different chemotype classes. A variety of ligand and receptor-based virtual screening approaches are examined, using combinations of individual templates 2D structures of known actives, a cocrystallized ligand, a receptor structure, or a cocrystallized ligand-biased receptor structure. We examine several data fusion approaches to combine the results of the individual virtual screens. In doing so, we show that excellent chemotype enrichment is achieved in both single target ligand-based and receptor-based approaches, of approximately 17-fold over random on average at a false positive rate of 1%. We also show that using as much starting knowledge as possible improves chemotype enrichment, and that data fusion using Pareto ranking is an effective method to do this giving up to 50% improvement in enrichment over the single methods. Finally we show that if inactivity or decoy data is incorporated, automatically training the scoring function in FLAP improves recovery still further, with almost 2-fold improvement over the enrichments shown by the single methods. The results clearly demonstrate the utility of FLAP for virtual screening when either a limited or wide range of prior knowledge is available.
Related JoVE Video
Eight-plex iTRAQ analysis of variant metastatic human prostate cancer cells identifies candidate biomarkers of progression: An exploratory study.
Prostate
PUBLISHED: 07-13-2010
Show Abstract
Hide Abstract
Due to the heterogeneity in the biological behavior of prostate cancer, biomarkers that can reliably distinguish indolent from aggressive disease are urgently needed to inform treatment choices.
Related JoVE Video
Microvascular endothelial cell responses in vitro and in vivo: modulation by zoledronic acid and paclitaxel?
J. Vasc. Res.
PUBLISHED: 04-30-2010
Show Abstract
Hide Abstract
The cytotoxic agent paclitaxel and the anti-resorptive drug zoledronic acid are used in the early and advanced breast cancer setting, respectively. Both agents have been demonstrated to have anti-tumour and anti-endothelial actions. Combining paclitaxel with zoledronic acid induces a synergistic increase in apoptotic breast cancer cell death in vitro, suggesting an increased anti-tumour effect in vivo, but any specific effects on the normal microvasculature and potential side-effects of this combination remain to be established.
Related JoVE Video
A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population.
Antonis C Antoniou, Xianshu Wang, Zachary S Fredericksen, Lesley McGuffog, Robert Tarrell, Olga M Sinilnikova, Sue Healey, Jonathan Morrison, Christiana Kartsonaki, Timothy Lesnick, Maya Ghoussaini, Daniel Barrowdale, , Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Diana Eccles, D Gareth Evans, Ros Eeles, Louise Izatt, Carol Chu, Fiona Douglas, Joan Paterson, Dominique Stoppa-Lyonnet, Claude Houdayer, Sylvie Mazoyer, Sophie Giraud, Christine Lasset, Audrey Remenieras, Olivier Caron, Agnès Hardouin, Pascaline Berthet, Frans B L Hogervorst, Matti A Rookus, Agnes Jager, Ans van den Ouweland, Nicoline Hoogerbrugge, Rob B van der Luijt, Hanne Meijers-Heijboer, Encarna B Gomez Garcia, Peter Devilee, Maaike P G Vreeswijk, Jan Lubiński, Anna Jakubowska, Jacek Gronwald, Tomasz Huzarski, Tomasz Byrski, Bohdan Górski, Cezary Cybulski, Amanda B Spurdle, Helene Holland, David E Goldgar, Esther M John, John L Hopper, Melissa Southey, Saundra S Buys, Mary B Daly, Mary-Beth Terry, Rita K Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Sabine Preisler-Adams, Norbert Arnold, Dieter Niederacher, Christian Sutter, Susan M Domchek, Katherine L Nathanson, Timothy Rebbeck, Joanne L Blum, Marion Piedmonte, Gustavo C Rodriguez, Katie Wakeley, John F Boggess, Jack Basil, Stephanie V Blank, Eitan Friedman, Bella Kaufman, Yael Laitman, Roni Milgrom, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, Tomas Kirchhoff, Joseph Vijai, Mia M Gaudet, David Altshuler, Candace Guiducci, Niklas Loman, Katja Harbst, Johanna Rantala, Hans Ehrencrona, Anne-Marie Gerdes, Mads Thomassen, Lone Sunde, Paolo Peterlongo, Siranoush Manoukian, Bernardo Bonanni, Alessandra Viel, Paolo Radice, Trinidad Caldés, Miguel de la Hoya, Christian F Singer, Anneliese Fink-Retter, Mark H Greene, Phuong L Mai, Jennifer T Loud, Lucia Guidugli, Noralane M Lindor, Thomas V O Hansen, Finn C Nielsen, Ignacio Blanco, Conxi Lazaro, Judy Garber, Susan J Ramus, Simon A Gayther, Catherine Phelan, Stephen Narod, Csilla I Szabo, Javier Benitez, Ana Osorio, Heli Nevanlinna, Tuomas Heikkinen, Maria A Caligo, Mary S Beattie, Ute Hamann, Andrew K Godwin, Marco Montagna, Cinzia Casella, Susan L Neuhausen, Beth Y Karlan, Nadine Tung, Amanda E Toland, Jeffrey Weitzel, Olofunmilayo Olopade, Jacques Simard, Penny Soucy, Wendy S Rubinstein, Adalgeir Arason, Gad Rennert, Nicholas G Martin, Grant W Montgomery, Jenny Chang-Claude, Dieter Flesch-Janys, Hiltrud Brauch, Gianluca Severi, Laura Baglietto, Angela Cox, Simon S Cross, Penelope Miron, Sue M Gerty, William Tapper, Drakoulis Yannoukakos, George Fountzilas, Peter A Fasching, Matthias W Beckmann, Isabel Dos Santos Silva, Julian Peto, Diether Lambrechts, Robert Paridaens, Thomas Rüdiger, Asta Försti, Robert Winqvist, Katri Pylkäs, Robert B Diasio, Adam M Lee, Jeanette Eckel-Passow, Celine Vachon, Fiona Blows, Kristy Driver, Alison Dunning, Paul P D Pharoah, Kenneth Offit, V Shane Pankratz, Hakon Hakonarson, Georgia Chenevix-Trench, Douglas F Easton, Fergus J Couch.
Nat. Genet.
PUBLISHED: 03-30-2010
Show Abstract
Hide Abstract
Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P(trend) = 2.3 × 10?? to P(trend) = 3.9 × 10??), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P(trend) = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P(trend) = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (P(trend) = 1 × 10??) to P(trend) = 8 × 10??; rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P(trend) = 1.1 × 10??
Related JoVE Video
Characterisation and expression of SPLUNC2, the human orthologue of rodent parotid secretory protein.
Histochem. Cell Biol.
PUBLISHED: 05-16-2009
Show Abstract
Hide Abstract
We recently described the Palate Lung Nasal Clone (PLUNC) family of proteins as an extended group of proteins expressed in the upper airways, nose and mouth. Little is known about these proteins, but they are secreted into the airway and nasal lining fluids and saliva where, due to their structural similarity with lipopolysaccharide-binding protein and bactericidal/permeability-increasing protein, they may play a role in the innate immune defence. We now describe the generation and characterisation of novel affinity-purified antibodies to SPLUNC2, and use them to determine the expression of this, the major salivary gland PLUNC. Western blotting showed that the antibodies identified a number of distinct protein bands in saliva, whilst immunohistochemical analysis demonstrated protein expression in serous cells of the major salivary glands and in the ductal lumens as well as in cells of minor mucosal glands. Antibodies directed against distinct epitopes of the protein yielded different staining patterns in both minor and major salivary glands. Using RT-PCR of tissues from the oral cavity, coupled with EST analysis, we showed that the gene undergoes alternative splicing using two 5 non-coding exons, suggesting that the gene is regulated by alternative promoters. Comprehensive RACE analysis using salivary gland RNA as template failed to identify any additional exons. Analysis of saliva showed that SPLUNC2 is subject to N-glycosylation. Thus, our study shows that multiple SPLUNC2 isoforms are found in the oral cavity and suggest that these proteins may be differentially regulated in distinct tissues where they may function in the innate immune response.
Related JoVE Video
Visualisation of cyclic and multi-branched molecules with VMD.
J. Mol. Graph. Model.
PUBLISHED: 03-22-2009
Show Abstract
Hide Abstract
We report the addition of two visualisation algorithms, termed PaperChain and Twister, to the freely available Visual Molecular Dynamics (VMD) package. These algorithms produce visualisations of complex cyclic molecules and multi-branched polysaccharides and are a generalization and optimization of those we previously developed in a standalone package for carbohydrates. PaperChain highlights each ring in a molecular structure with a polygon, which is coloured according to the ring pucker. Twister traces glycosidic bonds with a ribbon that twists according to the relative orientation of successive sugar residues. Combination of these novel algorithms and new ring selection statements with the large set of visualisations already available in VMD allows for unprecedented flexibility in the level of detail displayed for glycoconjugate, glycoprotein and carbohydrate-binding protein structures, as well as other cyclic structures. We highlight the efficacy of these algorithms with selected illustrative examples, clearly demonstrating the value of the new visualisations, not only for structure validation, but also for facilitating insights into molecular structure and mechanism.
Related JoVE Video
SHOP: a method for structure-based fragment and scaffold hopping.
ChemMedChem
PUBLISHED: 01-20-2009
Show Abstract
Hide Abstract
A new method for fragment and scaffold replacement is presented that generates new families of compounds with biological activity, using GRID molecular interaction fields (MIFs) and the crystal structure of the targets. In contrast to virtual screening strategies, this methodology aims only to replace a fragment of the original molecule, maintaining the other structural elements that are known or suspected to have a critical role in ligand binding. First, we report a validation of the method, recovering up to 95% of the original fragments searched among the top-five proposed solutions, using 164 fragment queries from 11 diverse targets. Second, six key customizable parameters are investigated, concluding that filtering the receptor MIF using the co-crystallized ligand atom type has the greatest impact on the ranking of the proposed solutions. Finally, 11 examples using more realistic scenarios have been performed; diverse chemotypes are returned, including some that are similar to compounds that are known to bind to similar targets.
Related JoVE Video
Molecular fields in drug discovery: getting old or reaching maturity?
Drug Discov. Today
PUBLISHED: 01-14-2009
Show Abstract
Hide Abstract
With GRID first published 23 years ago, and CoMFA 20 years ago, the two most widely known methods that apply molecular fields to drug discovery are now into their third decade. Are molecular-field-based methods still applicable to modern drug discovery? Are they old and outdated? Or are they maturing into their full potential?
Related JoVE Video
Tautomer enumeration and stability prediction for virtual screening on large chemical databases.
J Chem Inf Model
PUBLISHED: 01-07-2009
Show Abstract
Hide Abstract
Tautomeric rearrangements affect the results of cheminformatics applications that depend on the knowledge of the 2D or 3D structure of a compound, such as tools for database searches, fingerprint generation, virtual screening, and physical-chemical properties prediction. In this paper we present TauThor, a tool to enumerate tautomers and predict tautomer stability in the aqueous medium. The enumeration is based on a recursive process that generates tautomers according to the general scheme HX-Y=Z left harpoon over right harpoon X=Y-ZH. The stability of a tautomer is calculated by using a library of 145 fragments associated with experimental tautomeric percentages in water and a pK(a) based-method that utilizes pK(a) values predicted by MoKa. Predicted tautomeric ratios based on pK(a) calculations were benchmarked against literature data for a set of eleven compounds. The FDA approved drugs database, the NCI database and two vendor databases - Specs Screening Library and Asinex Gold Collection - were used to illustrate the impact of tautomerism on chemical libraries and to evaluate the relative occurrences of alternative tautomeric forms.
Related JoVE Video
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.
Show Abstract
Hide Abstract
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.
Related JoVE Video
Mini-Med School: promoting awareness of medicine as a career for suburban and rural high-school students.
ANZ J Surg
Show Abstract
Hide Abstract
There is a global shortage of medical manpower. One approach to resolve such deficiencies is to effectively promote health careers to high-school students. Summer programmes held by medical faculties provide ideal opportunities for pre-medical students to examine the possible career opportunities in medicine.
Related JoVE Video
Inhibition of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension.
J. Exp. Med.
Show Abstract
Hide Abstract
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by the progressive narrowing and occlusion of small pulmonary arteries. Current therapies fail to fully reverse this vascular remodeling. Identifying key pathways in disease pathogenesis is therefore required for the development of new-targeted therapeutics. We have previously reported tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) immunoreactivity within pulmonary vascular lesions from patients with idiopathic PAH and animal models. Because TRAIL can induce both endothelial cell apoptosis and smooth muscle cell proliferation in the systemic circulation, we hypothesized that TRAIL is an important mediator in the pathogenesis of PAH. We demonstrate for the first time that TRAIL is a potent stimulus for pulmonary vascular remodeling in human cells and rodent models. Furthermore, antibody blockade or genetic deletion of TRAIL prevents the development of PAH in three independent rodent models. Finally, anti-TRAIL antibody treatment of rodents with established PAH reverses pulmonary vascular remodeling by reducing proliferation and inducing apoptosis, improves hemodynamic indices, and significantly increases survival. These preclinical investigations are the first to demonstrate the importance of TRAIL in PAH pathogenesis and highlight its potential as a novel therapeutic target to direct future translational therapies.
Related JoVE Video
A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11.
Afshan Siddiq, Fergus J Couch, Gary K Chen, Sara Lindstrom, Diana Eccles, Robert C Millikan, Kyriaki Michailidou, Daniel O Stram, Lars Beckmann, Suhn Kyong Rhie, Christine B Ambrosone, Kristiina Aittomäki, Pilar Amiano, Carmel Apicella, , Laura Baglietto, Elisa V Bandera, Matthias W Beckmann, Christine D Berg, Leslie Bernstein, Carl Blomqvist, Hiltrud Brauch, Louise Brinton, Quang M Bui, Julie E Buring, Saundra S Buys, Daniele Campa, Jane E Carpenter, Daniel I Chasman, Jenny Chang-Claude, Constance Chen, Francoise Clavel-Chapelon, Angela Cox, Simon S Cross, Kamila Czene, Sandra L Deming, Robert B Diasio, W Ryan Diver, Alison M Dunning, Lorraine Durcan, Arif B Ekici, Peter A Fasching, Heather Spencer Feigelson, Laura Fejerman, Jonine D Figueroa, Olivia Fletcher, Dieter Flesch-Janys, Mia M Gaudet, Susan M Gerty, Jorge L Rodriguez-Gil, Graham G Giles, Carla H van Gils, Andrew K Godwin, Nikki Graham, Dario Greco, Per Hall, Susan E Hankinson, Arndt Hartmann, Rebecca Hein, Judith Heinz, Robert N Hoover, John L Hopper, Jennifer J Hu, Scott Huntsman, Sue A Ingles, Astrid Irwanto, Claudine Isaacs, Kevin B Jacobs, Esther M John, Christina Justenhoven, Rudolf Kaaks, Laurence N Kolonel, Gerhard A Coetzee, Mark Lathrop, Loic Le Marchand, Adam M Lee, I-Min Lee, Timothy Lesnick, Peter Lichtner, Jianjun Liu, Eiliv Lund, Enes Makalic, Nicholas G Martin, Catriona A McLean, Hanne Meijers-Heijboer, Alfons Meindl, Penelope Miron, Kristine R Monroe, Grant W Montgomery, Bertram Müller-Myhsok, Stefan Nickels, Sarah J Nyante, Curtis Olswold, Kim Overvad, Domenico Palli, Daniel J Park, Julie R Palmer, Harsh Pathak, Julian Peto, Paul Pharoah, Nazneen Rahman, Fernando Rivadeneira, Daniel F Schmidt, Rita K Schmutzler, Susan Slager, Melissa C Southey, Kristen N Stevens, Hans-Peter Sinn, Michael F Press, Eric Ross, Elio Riboli, Paul M Ridker, Fredrick R Schumacher, Gianluca Severi, Isabel Dos Santos Silva, Jennifer Stone, Malin Sund, William J Tapper, Michael J Thun, Ruth C Travis, Clare Turnbull, André G Uitterlinden, Quinten Waisfisz, Xianshu Wang, Zhaoming Wang, Joellen Weaver, Rüdiger Schulz-Wendtland, Lynne R Wilkens, David Van Den Berg, Wei Zheng, Regina G Ziegler, Elad Ziv, Heli Nevanlinna, Douglas F Easton, David J Hunter, Brian E Henderson, Stephen J Chanock, Montserrat Garcia-Closas, Peter Kraft, Christopher A Haiman, Celine M Vachon.
Hum. Mol. Genet.
Show Abstract
Hide Abstract
Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ? 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
Related JoVE Video
GRID-based three-dimensional pharmacophores I: FLAPpharm, a novel approach for pharmacophore elucidation.
J Chem Inf Model
Show Abstract
Hide Abstract
Pharmacophore elucidation approaches are routinely used in drug discovery, primarily with the aim of determining the three-dimensional arrangement of common features shared by ligands interacting at the site of interest; these features can then be used to investigate the structure-activity relationship between the ligands and also to screen for other molecules possessing the relevant features. Here we present a novel approach based on GRID molecular interaction fields and the derivative method FLAP that has been previously described, which provides a common reference framework to compare both small molecule ligands and macromolecular protein targets. Unlike classical pharmacophore elucidation approaches that extract simplistic molecular features, determine those which are common across the data set, and use these features to align the structures, FLAPpharm first aligns the structures and subsequently extracts the common interacting features in terms of their molecular interaction fields, pseudofields, and atomic points, representing the common pharmacophore as a more comprehensive pharmacophoric pseudomolecule. The approach is applied to a number of data sets to investigate performance in terms of reproducing the X-ray crystallography-based alignment, in terms of its discriminatory ability when applied to virtual screening and also to illustrate its ability to explain alternative binding modes. In part two of this publication, a comprehensive benchmark data set for pharmacophore elucidation is presented and the performance of FLAPpharm discussed.
Related JoVE Video
GRID-based three-dimensional pharmacophores II: PharmBench, a benchmark data set for evaluating pharmacophore elucidation methods.
J Chem Inf Model
Show Abstract
Hide Abstract
To date, published pharmacophore elucidation approaches typically use a handful of data sets for validation: here, we have assembled a data set for 81 targets, containing 960 ligands aligned using their cocrystallized protein targets, to provide the experimental "gold standard". The two-dimensional structures are also assembled to remove conformational bias; an ideal method would be able to take these structures as input, find the common features, and reproduce the bioactive conformations and their alignments to correspond with the X-ray-determined gold standard alignments. Here we present this data set and describe three objective measures to evaluate performance: the ability to identify the bioactive conformation, the ability to identify and correctly align this conformation for 50% of the molecules in each data set, and the pharmacophoric field similarity. We have applied this validation methodology to our pharmacophore elucidation method FLAPpharm, that is published in the first paper of this series and discuss the limitations of the data set and objective success criteria. Starting from two-dimensional structures and producing unbiased models, FLAPpharm was able to identify the bioactive conformations for 67% of the ligands and also to produce successful models according to the second metric for 67% of the Pharmbench data sets. Inspection of the unsuccessful models highlighted the limitation of this root mean square (rms)-derived metric, since many were found to be pharmacophorically reasonable, increasing the overall success rate to 83%. The PharmBench data set is available at http://www.moldiscovery.com/PharmBench , along with a web service to enable users to score model alignments coming from external methods in the same way that we have presented here and, therefore, establishes a pharmacophore elucidation benchmark data set available to be used by the community.
Related JoVE Video
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
Show Abstract
Hide Abstract
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.
Related JoVE Video
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.
Show Abstract
Hide Abstract
Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).
Related JoVE Video
A zebrafish model to study and therapeutically manipulate hypoxia signaling in tumorigenesis.
Cancer Res.
Show Abstract
Hide Abstract
Hypoxic signaling is a central modulator of cellular physiology in cancer. Core members of oxygen-sensing pathway including the von Hippel-Lindau tumor suppressor protein (pVHL) and the hypoxia inducible factor (HIF) transcription factors have been intensively studied, but improved organismal models might speed advances for both pathobiologic understanding and therapeutic modulation. To study HIF signaling during tumorigenesis and development in zebrafish, we developed a unique in vivo reporter for hypoxia, expressing EGFP driven by prolyl hydroxylase 3 (phd3) promoter/regulatory elements. Modulation of HIF pathway in Tg(phd3::EGFP) embryos showed a specific role for hypoxic signaling in the transgene activation. Zebrafish vhl mutants display a systemic hypoxia response, reflected by strong and ubiquitous transgene expression. In contrast to human VHL patients, heterozygous Vhl mice and vhl zebrafish are not predisposed to cancer. However, upon exposure to dimethylbenzanthracene (DMBA), the vhl heterozygous fish showed an increase in the occurrence of hepatic and intestinal tumors, a subset of which exhibited strong transgene expression, suggesting loss of Vhl function in these tumor cells. Compared with control fish, DMBA-treated vhl heterozygous fish also showed an increase in proliferating cell nuclear antigen-positive renal tubules. Taken together, our findings establish Vhl as a genuine tumor suppressor in zebrafish and offer this model as a tool to noninvasively study VHL and HIF signaling during tumorigenesis and development.
Related JoVE Video
Duodenal bulb biopsies for diagnosing adult celiac disease: is there an optimal biopsy site?
Gastrointest. Endosc.
Show Abstract
Hide Abstract
Recent studies highlight the role of duodenal bulb biopsy in the diagnosis of celiac disease.
Related JoVE Video
The role of genetic breast cancer susceptibility variants as prognostic factors.
Peter A Fasching, Paul D P Pharoah, Angela Cox, Heli Nevanlinna, Stig E Bojesen, Thomas Karn, Annegien Broeks, Flora E van Leeuwen, Laura J Van't Veer, Renate Udo, Alison M Dunning, Dario Greco, Kristiina Aittomäki, Carl Blomqvist, Mitul Shah, Børge G Nordestgaard, Henrik Flyger, John L Hopper, Melissa C Southey, Carmel Apicella, Montserrat Garcia-Closas, Mark Sherman, Jolanta Lissowska, Caroline Seynaeve, Petra E A Huijts, Rob A E M Tollenaar, Argyrios Ziogas, Arif B Ekici, Claudia Rauh, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Irene L Andrulis, Hilmi Ozcelik, Anna-Marie Mulligan, Gord Glendon, Per Hall, Kamila Czene, Jianjun Liu, Jenny Chang-Claude, Shan Wang-Gohrke, Ursula Eilber, Stefan Nickels, Thilo Dörk, Maria Schiekel, Michael Bremer, Tjoung-Won Park-Simon, Graham G Giles, Gianluca Severi, Laura Baglietto, Maartje J Hooning, John W M Martens, Agnes Jager, Mieke Kriege, Annika Lindblom, Sara Margolin, Fergus J Couch, Kristen N Stevens, Janet E Olson, Matthew Kosel, Simon S Cross, Sabapathy P Balasubramanian, Malcolm W R Reed, Alexander Miron, Esther M John, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Georgia Chenevix-Trench, , Diether Lambrechts, Anne-Sophie Dieudonné, Sigrid Hatse, Erik Van Limbergen, Javier Benitez, Roger L Milne, M Pilar Zamora, Jose Ignacio Arias Perez, Bernardo Bonanni, Bernard Peissel, Bernard Loris, Paolo Peterlongo, Preetha Rajaraman, Sara J Schonfeld, Hoda Anton-Culver, Peter Devilee, Matthias W Beckmann, Dennis J Slamon, Kelly-Anne Phillips, Jonine D Figueroa, Manjeet K Humphreys, Douglas F Easton, Marjanka K Schmidt.
Hum. Mol. Genet.
Show Abstract
Hide Abstract
Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.
Related JoVE Video
Deficiency of tumour necrosis factor-related apoptosis-inducing ligand exacerbates lung injury and fibrosis.
Thorax
Show Abstract
Hide Abstract
The death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) shows considerable clinical promise as a therapeutic agent. TRAIL induces leukocyte apoptosis, reducing acute inflammatory responses in the lung. It is not known whether TRAIL modifies chronic lung injury or whether TRAIL has a role in human idiopathic pulmonary fibrosis (IPF). We therefore explored the capacity of TRAIL to modify chronic inflammatory lung injury and studied TRAIL expression in patients with IPF.
Related JoVE Video
11q13 is a susceptibility locus for hormone receptor positive breast cancer.
Diether Lambrechts, Thérèse Truong, Christina Justenhoven, Manjeet K Humphreys, Jean Wang, John L Hopper, Gillian S Dite, Carmel Apicella, Melissa C Southey, Marjanka K Schmidt, Annegien Broeks, Sten Cornelissen, Richard van Hien, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Nicola Miller, Roger L Milne, M Pilar Zamora, Jose Ignacio Arias Perez, Javier Benitez, Ute Hamann, Yon-Dschun Ko, Thomas Brüning, , Jenny Chang-Claude, Ursel Eilber, Rebecca Hein, Stefan Nickels, Dieter Flesch-Janys, Shan Wang-Gohrke, Esther M John, Alexander Miron, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Georgia Chenevix-Trench, Jonathan Beesley, Xiaoqing Chen, Florence Menegaux, Emilie Cordina-Duverger, Chen-Yang Shen, Jyh-Cherng Yu, Pei-Ei Wu, Ming-Feng Hou, Irene L Andrulis, Teresa Selander, Gord Glendon, Anna Marie Mulligan, Hoda Anton-Culver, Argyrios Ziogas, Kenneth R Muir, Artitaya Lophatananon, Suthee Rattanamongkongul, Puttisak Puttawibul, Michael Jones, Nicholas Orr, Alan Ashworth, Anthony Swerdlow, Gianluca Severi, Laura Baglietto, Graham Giles, Melissa Southey, Federik Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Betul T Yesilyurt, Patrick Neven, Robert Paridaens, Hans Wildiers, Hermann Brenner, Heiko Muller, Volker Arndt, Christa Stegmaier, Alfons Meindl, Sarah Schott, Claus R Bartram, Rita K Schmutzler, Angela Cox, Ian W Brock, Graeme Elliott, Simon S Cross, Peter A Fasching, Ruediger Schulz-Wendtland, Arif B Ekici, Matthias W Beckmann, Olivia Fletcher, Nichola Johnson, Isabel dos Santos Silva, Julian Peto, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Thilo Dörk, Peter Schürmann, Michael Bremer, Peter Hillemanns, Natalia V Bogdanova, Natalia N Antonenkova, Yuri I Rogov, Johann H Karstens, Elza Khusnutdinova, Marina Bermisheva, Darya Prokofieva, Shamil Gancev, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska, Katarzyna Durda, Børge G Nordestgaard, Stig E Bojesen, Charlotte Lanng, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Loris Bernard, Fergus J Couch, Janet E Olson, Xianshu Wang, Zachary Fredericksen, Grethe Grenaker Alnaes, Vessela Kristensen, Anne-Lise Børresen-Dale, Peter Devilee, Robert A E M Tollenaar, Caroline M Seynaeve, Maartje J Hooning, Montserrat Garcia-Closas, Stephen J Chanock, Jolanta Lissowska, Mark E Sherman, Per Hall, Jianjun Liu, Kamila Czene, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Annika Lindblom, Sara Margolin, Alison M Dunning, Paul D P Pharoah, Douglas F Easton, Pascal Guénel, Hiltrud Brauch.
Hum. Mutat.
Show Abstract
Hide Abstract
A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P ? 3 × 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.
Related JoVE Video
iTRAQ identification of candidate serum biomarkers associated with metastatic progression of human prostate cancer.
PLoS ONE
Show Abstract
Hide Abstract
A major challenge in the management of patients with prostate cancer is identifying those individuals at risk of developing metastatic disease, as in most cases the disease will remain indolent. We analyzed pooled serum samples from 4 groups of patients (n?=?5 samples/group), collected prospectively and actively monitored for a minimum of 5 yrs. Patients groups were (i) histological diagnosis of benign prostatic hyperplasia with no evidence of cancer BPH, (ii) localised cancer with no evidence of progression, non-progressing (iii) localised cancer with evidence of biochemical progression, progressing, and (iv) bone metastasis at presentation metastatic. Pooled samples were immuno-depleted of the 14 most highly abundant proteins and analysed using a 4-plex iTRAQ approach. Overall 122 proteins were identified and relatively quantified. Comparisons of progressing versus non-progressing groups identified the significant differential expression of 25 proteins (p<0.001). Comparisons of metastatic versus progressing groups identified the significant differential expression of 23 proteins. Mapping the differentially expressed proteins onto the prostate cancer progression pathway revealed the dysregulated expression of individual proteins, pairs of proteins and panels of proteins to be associated with particular stages of disease development and progression. The median immunostaining intensity of eukaryotic translation elongation factor 1 alpha 1 (eEF1A1), one of the candidates identified, was significantly higher in osteoblasts in close proximity to metastatic tumour cells compared with osteoblasts in control bone (p?=?0.0353, Mann Whitney U). Our proteomic approach has identified leads for potentially useful serum biomarkers associated with the metastatic progression of prostate cancer. The panels identified, including eEF1A1 warrant further investigation and validation.
Related JoVE Video
19p13.1 is a triple-negative-specific breast cancer susceptibility locus.
Kristen N Stevens, Zachary Fredericksen, Celine M Vachon, Xianshu Wang, Sara Margolin, Annika Lindblom, Heli Nevanlinna, Dario Greco, Kristiina Aittomäki, Carl Blomqvist, Jenny Chang-Claude, Alina Vrieling, Dieter Flesch-Janys, Hans-Peter Sinn, Shan Wang-Gohrke, Stefan Nickels, Hiltrud Brauch, , Yon-Dschun Ko, Hans-Peter Fischer, Rita K Schmutzler, Alfons Meindl, Claus R Bartram, Sarah Schott, Christoph Engel, Andrew K Godwin, Joellen Weaver, Harsh B Pathak, Priyanka Sharma, Hermann Brenner, Heiko Muller, Volker Arndt, Christa Stegmaier, Penelope Miron, Drakoulis Yannoukakos, Alexandra Stavropoulou, George Fountzilas, Helen J Gogas, Ruth Swann, Miriam Dwek, Annie Perkins, Roger L Milne, Javier Benitez, María Pilar Zamora, Jose Ignacio Arias Perez, Stig E Bojesen, Sune F Nielsen, Børge G Nordestgaard, Henrik Flyger, Pascal Guénel, Thérèse Truong, Florence Menegaux, Emilie Cordina-Duverger, Barbara Burwinkel, Frederick Marme, Andreas Schneeweiss, Christof Sohn, Elinor Sawyer, Ian Tomlinson, Michael J Kerin, Julian Peto, Nichola Johnson, Olivia Fletcher, Isabel Dos Santos Silva, Peter A Fasching, Matthias W Beckmann, Arndt Hartmann, Arif B Ekici, Artitaya Lophatananon, Kenneth Muir, Puttisak Puttawibul, Surapon Wiangnon, Marjanka K Schmidt, Annegien Broeks, Linde M Braaf, Efraim H Rosenberg, John L Hopper, Carmel Apicella, Daniel J Park, Melissa C Southey, Anthony J Swerdlow, Alan Ashworth, Nicholas Orr, Minouk J Schoemaker, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina Clarke Dur, Chen-Yang Shen, Jyh-Cherng Yu, Huan-Ming Hsu, Chia-Ni Hsiung, Ute Hamann, Thomas Dünnebier, Thomas Rüdiger, Hans Ulrich Ulmer, Paul P Pharoah, Alison M Dunning, Manjeet K Humphreys, Qin Wang, Angela Cox, Simon S Cross, Malcom W Reed, Per Hall, Kamila Czene, Christine B Ambrosone, Foluso Ademuyiwa, Helena Hwang, Diana M Eccles, Montserrat Garcia-Closas, Jonine D Figueroa, Mark E Sherman, Jolanta Lissowska, Peter Devilee, Caroline Seynaeve, Rob A E M Tollenaar, Maartje J Hooning, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Esther M John, Alexander Miron, Grethe Grenaker Alnæs, Vessela Kristensen, Anne-Lise Børresen-Dale, Graham G Giles, Laura Baglietto, Catriona A McLean, Gianluca Severi, Matthew L Kosel, V S Pankratz, Susan Slager, Janet E Olson, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Diether Lambrechts, Sigrid Hatse, Anne-Sophie Dieudonné, Marie-Rose Christiaens, Georgia Chenevix-Trench, Jonathan Beesley, Xiaoqing Chen, Arto Mannermaa, Veli-Matti Kosma, Jaana M Hartikainen, Ylermi Soini, Douglas F Easton, Fergus J Couch.
Cancer Res.
Show Abstract
Hide Abstract
The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P = 3.31 × 10(-13)]. Thus, 19p13.1 is the first triple-negative-specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways.
Related JoVE Video
The inhibition of extended spectrum ?-lactamases: hits and leads.
Curr. Med. Chem.
Show Abstract
Hide Abstract
The ongoing emergence of bacterial strains resistant to even third- and fourth-generation ?-lactam antibiotics is one of the most pressing and challenging issues in clinical therapy. Furthermore, under the pressure of antibiotics used ubiquitously over the last 80 years, functional mutations and new resistances are continuously increasing. Therefore, new drugs and new approaches to the infections produced by multidrug-resistant Gram-negative bacteria are categorically necessary and expected by the scientific community. This review describes the most deleterious known extended-spectrum ?-lactamases and the molecules now available for targeting bacterial infections. The active-site chemical and geometric properties that are potentially exploitable for the design of both broad-spectrum and selective compounds are described.
Related JoVE Video

What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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

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