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Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

INTRODUCTION Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is …s currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. METHODS We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. RESULTS The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 \times 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. CONCLUSIONS The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

Authors: Anna Marie Mulligan, Fergus J. Couch, Daniel Barrowdale, Susan M. Domchek, Diana Eccles, Heli Nevanlinna, Susan J. Ramus, Mark Robson, Mark Sherman, Amanda B. Spurdle, Barbara Wappenschmidt, Andrew Lee, Lesley McGuffog, Sue Healey, Olga M. Sinilnikova, Ramunas Janavicius, Thomas vO Hansen, Finn C. Nielsen, Bent Ejlertsen, Ana Osorio, Iván Muñoz-Repeto, Mercedes Durán, Javier Godino, Maroulio Pertesi, Javier Benítez, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Elisa Cattaneo, Bernardo Bonanni, Alessandra Viel, Barbara Pasini, Laura Papi, Laura Ottini, Antonella Savarese, Loris Bernard, Paolo Radice, Ute Hamann, Martijn Verheus, Hanne E. J. Meijers-Heijboer, Juul Wijnen, Encarna B. Gómez García, Marcel R. Nelen, C. Marleen Kets, Caroline Seynaeve, Madeleine M. A. Tilanus-Linthorst, Rob B. van der Luijt, Theo van Os, Matti Rookus, Debra Frost, J. Louise Jones, D. Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Julian Adlard, Rosemarie Davidson, Jackie Cook, Alan Donaldson, Huw Dorkins, Helen Gregory, Jacqueline Eason, Catherine Houghton, Julian Barwell, Lucy E. Side, Emma McCann, Alex Murray, Susan Peock, Andrew K. Godwin, Rita K. Schmutzler, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Ina Ruehl, Norbert Arnold, Dieter Niederacher, Christian Sutter, Helmut Deissler, Dorothea Gadzicki, Karin Kast, Sabine Preisler-Adams, Raymonda Varon-Mateeva, Ines Schoenbuchner, Britta Fiebig, Wolfram Heinritz, Dieter Schäfer, Heidrun Gevensleben, Virginie Caux-Moncoutier, Marion Fassy-Colcombet, François Cornelis, Sylvie Mazoyer, Mélanie Léoné, Nadia Boutry-Kryza, Agnès Hardouin, Pascaline Berthet, Danièle Muller, Jean-Pierre Fricker, Isabelle Mortemousque, Pascal Pujol, Isabelle Coupier, Marine Lebrun, Caroline Kientz, Michel Longy, Nicolas Sevenet, Dominique Stoppa-Lyonnet, Claudine Isaacs, Trinidad Caldes, Miguel de La Hoya, Tuomas Heikkinen, Kristiina Aittomäki, Ignacio Blanco, Conxi Lazaro, Rosa B. Barkardottir, Penny Soucy, Martine Dumont, Jacques Simard, Marco Montagna, Silvia Tognazzo, Emma D’Andrea, Stephen Fox, Max Yan, Tim Rebbeck, Olufunmilayo Olopade, Jeffrey N. Weitzel, Henry T. Lynch, Patricia A. Ganz, Gail E. Tomlinson, Xianshu Wang, Zachary Fredericksen, Vernon S. Pankratz, Noralane M. Lindor, Csilla Szabo, Kenneth Offit, Rita Sakr, Mia Gaudet, Jasmine Bhatia, Noah Kauff, Christian F. Singer, Muy-Kheng Tea, Daphne Gschwantler-Kaulich, Anneliese Fink-Retter, Phuong L. Mai, Mark H. Greene, Evgeny Imyanitov, Frances P. O’Malley, Hilmi Ozcelik, Gordon Glendon, Amanda E. Toland, Anne-Marie Gerdes, Mads Thomassen, Torben A. Kruse, Uffe Birk Jensen, Anne-Bine Skytte, Maria A. Caligo, Maria Soller, Karin Henriksson, von Anna Wachenfeldt, Brita Arver, Marie Stenmark-Askmalm, Per Karlsson, Yuan Chun Ding, Susan L. Neuhausen, Mary Beattie, Paul D. P. Pharoah, Kirsten B. Moysich, Katherine L. Nathanson, Beth Y. Karlan, Jenny Gross, Esther M. John, Mary B. Daly, Saundra M. Buys, Melissa C. Southey, John L. Hopper, Mary Beth Terry, Wendy Chung, Alexander F. Miron, David Goldgar, Georgia Chenevix-Trench, Douglas F. Easton, Irene L. Andrulis, Antonis C. Antoniou

Date Published: 1st Dec 2011

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Mutations in the BRCA1 gene substantially increase a woman’s lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers … identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

Authors: David G. Cox, Jacques Simard, Daniel Sinnett, Yosr Hamdi, Penny Soucy, Manon Ouimet, Laure Barjhoux, Carole Verny-Pierre, Lesley McGuffog, Sue Healey, Csilla Szabo, Mark H. Greene, Phuong L. Mai, Irene L. Andrulis, Mads Thomassen, Anne-Marie Gerdes, Maria A. Caligo, Eitan Friedman, Yael Laitman, Bella Kaufman, Shani S. Paluch, Åke Borg, Per Karlsson, Marie Stenmark Askmalm, Gisela Barbany Bustinza, Katherine L. Nathanson, Susan M. Domchek, Timothy R. Rebbeck, Javier Benítez, Ute Hamann, Matti A. Rookus, Ans M. W. van den Ouweland, Margreet G. E. M. Ausems, Cora M. Aalfs, Christi J. van Asperen, Peter Devilee, Hans J. J. P. Gille, Susan Peock, Debra Frost, D. Gareth Evans, Ros Eeles, Louise Izatt, Julian Adlard, Joan Paterson, Jacqueline Eason, Andrew K. Godwin, Marie-Alice Remon, Virginie Moncoutier, Marion Gauthier-Villars, Christine Lasset, Sophie Giraud, Agnès Hardouin, Pascaline Berthet, Hagay Sobol, François Eisinger, Brigitte Bressac de Paillerets, Olivier Caron, Capucine Delnatte, David Goldgar, Alex Miron, Hilmi Ozcelik, Saundra Buys, Melissa C. Southey, Mary Beth Terry, Christian F. Singer, Anne-Catharina Dressler, Muy-Kheng Tea, Thomas v. O. Hansen, Oskar Johannsson, Marion Piedmonte, Gustavo C. Rodriguez, Jack B. Basil, Stephanie Blank, Amanda E. Toland, Marco Montagna, Claudine Isaacs, Ignacio Blanco, Simon A. Gayther, Kirsten B. Moysich, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Dieter Niederacher, Christian Sutter, Dorothea Gadzicki, Britta Fiebig, Trinidad Caldes, Rachel Laframboise, Heli Nevanlinna, Xiaoqing Chen, Jonathan Beesley, Amanda B. Spurdle, Susan L. Neuhausen, Yuan C. Ding, Fergus J. Couch, Xianshu Wang, Paolo Peterlongo, Siranoush Manoukian, Loris Bernard, Paolo Radice, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Olga M. Sinilnikova

Date Published: 1st Dec 2011

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide … association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 \times 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 \times 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

Authors: Antonis C. Antoniou, Christiana Kartsonaki, Olga M. Sinilnikova, Penny Soucy, Lesley McGuffog, Sue Healey, Andrew Lee, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Elisa Cattaneo, Monica Barile, Valeria Pensotti, Barbara Pasini, Riccardo Dolcetti, Giuseppe Giannini, Anna Laura Putignano, Liliana Varesco, Paolo Radice, Phuong L. Mai, Mark H. Greene, Irene L. Andrulis, Gord Glendon, Hilmi Ozcelik, Mads Thomassen, Anne-Marie Gerdes, Torben A. Kruse, Uffe Birk Jensen, Dorthe G. Crüger, Maria A. Caligo, Yael Laitman, Roni Milgrom, Bella Kaufman, Shani Paluch-Shimon, Eitan Friedman, Niklas Loman, Katja Harbst, Annika Lindblom, Brita Arver, Hans Ehrencrona, Beatrice Melin, Katherine L. Nathanson, Susan M. Domchek, Timothy Rebbeck, Ania Jakubowska, Jan Lubinski, Jacek Gronwald, Tomasz Huzarski, Tomasz Byrski, Cezary Cybulski, Bohdan Gorski, Ana Osorio, Teresa Ramón y Cajal, Florentia Fostira, Raquel Andrés, Javier Benitez, Ute Hamann, Frans B. Hogervorst, Matti A. Rookus, Maartje J. Hooning, Marcel R. Nelen, Rob B. van der Luijt, Theo A. M. van Os, Christi J. van Asperen, Peter Devilee, Hanne E. J. Meijers-Heijboer, Encarna B. Gómez Garcia, Susan Peock, Margaret Cook, Debra Frost, Radka Platte, Jean Leyland, D. Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Julian Adlard, Rosemarie Davidson, Diana Eccles, Kai-Ren Ong, Jackie Cook, Fiona Douglas, Joan Paterson, M. John Kennedy, Zosia Miedzybrodzka, Andrew Godwin, Dominique Stoppa-Lyonnet, Bruno Buecher, Muriel Belotti, Carole Tirapo, Sylvie Mazoyer, Laure Barjhoux, Christine Lasset, Dominique Leroux, Laurence Faivre, Myriam Bronner, Fabienne Prieur, Catherine Nogues, Etienne Rouleau, Pascal Pujol, Isabelle Coupier, Marc Frénay, John L. Hopper, Mary B. Daly, Mary B. Terry, Esther M. John, Saundra S. Buys, Yosuf Yassin, Alexander Miron, David Goldgar, Christian F. Singer, Muy-Kheng Tea, Georg Pfeiler, Anne Catharina Dressler, Thomas v. O. Hansen, Lars Jønson, Bent Ejlertsen, Rosa Bjork Barkardottir, Tomas Kirchhoff, Kenneth Offit, Marion Piedmonte, Gustavo Rodriguez, Laurie Small, John Boggess, Stephanie Blank, Jack Basil, Masoud Azodi, Amanda Ewart Toland, Marco Montagna, Silvia Tognazzo, Simona Agata, Evgeny Imyanitov, Ramunas Janavicius, Conxi Lazaro, Ignacio Blanco, Paul D. P. Pharoah, Lara Sucheston, Beth Y. Karlan, Christine S. Walsh, Edith Olah, Aniko Bozsik, Soo-Hwang Teo, Joyce L. Seldon, Mary S. Beattie, Elizabeth J. van Rensburg, Michelle D. Sluiter, Orland Diez, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Ina Ruehl, Raymonda Varon-Mateeva, Karin Kast, Helmut Deissler, Dieter Niederacher, Norbert Arnold, Dorothea Gadzicki, Ines Schönbuchner, Trinidad Caldes, Miguel de La Hoya, Heli Nevanlinna, Kristiina Aittomäki, Martine Dumont, Jocelyne Chiquette, Marc Tischkowitz, Xiaoqing Chen, Jonathan Beesley, Amanda B. Spurdle, Susan L. Neuhausen, Yuan Chun Ding, Zachary Fredericksen, Xianshu Wang, Vernon S. Pankratz, Fergus Couch, Jacques Simard, Douglas F. Easton, Georgia Chenevix-Trench

Date Published: 15th Aug 2011

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations … of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 \times 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

Authors: Antonis C. Antoniou, Jonathan Beesley, Lesley McGuffog, Olga M. Sinilnikova, Sue Healey, Susan L. Neuhausen, Yuan Chun Ding, Timothy R. Rebbeck, Jeffrey N. Weitzel, Henry T. Lynch, Claudine Isaacs, Patricia A. Ganz, Gail Tomlinson, Olufunmilayo I. Olopade, Fergus J. Couch, Xianshu Wang, Noralane M. Lindor, Vernon S. Pankratz, Paolo Radice, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Monica Barile, Alessandra Viel, Anna Allavena, Valentina Dall’Olio, Paolo Peterlongo, Csilla I. Szabo, Michal Zikan, Kathleen Claes, Bruce Poppe, Lenka Foretova, Phuong L. Mai, Mark H. Greene, Gad Rennert, Flavio Lejbkowicz, Gord Glendon, Hilmi Ozcelik, Irene L. Andrulis, Mads Thomassen, Anne-Marie Gerdes, Lone Sunde, Dorthe Cruger, Uffe Birk Jensen, Maria Caligo, Eitan Friedman, Bella Kaufman, Yael Laitman, Roni Milgrom, Maya Dubrovsky, Shimrit Cohen, Ake Borg, Helena Jernström, Annika Lindblom, Johanna Rantala, Marie Stenmark-Askmalm, Beatrice Melin, Kate Nathanson, Susan Domchek, Ania Jakubowska, Jan Lubinski, Tomasz Huzarski, Ana Osorio, Adriana Lasa, Mercedes Durán, Maria-Isabel Tejada, Javier Godino, Javier Benitez, Ute Hamann, Mieke Kriege, Nicoline Hoogerbrugge, Rob B. van der Luijt, Christi J. van Asperen, Peter Devilee, E. J. Meijers-Heijboer, Marinus J. Blok, Cora M. Aalfs, Frans Hogervorst, Matti Rookus, Margaret Cook, Clare Oliver, Debra Frost, Don Conroy, D. Gareth Evans, Fiona Lalloo, Gabriella Pichert, Rosemarie Davidson, Trevor Cole, Jackie Cook, Joan Paterson, Shirley Hodgson, Patrick J. Morrison, Mary E. Porteous, Lisa Walker, M. John Kennedy, Huw Dorkins, Susan Peock, Andrew K. Godwin, Dominique Stoppa-Lyonnet, Antoine de Pauw, Sylvie Mazoyer, Valérie Bonadona, Christine Lasset, Hélène Dreyfus, Dominique Leroux, Agnès Hardouin, Pascaline Berthet, Laurence Faivre, Catherine Loustalot, Tetsuro Noguchi, Hagay Sobol, Etienne Rouleau, Catherine Nogues, Marc Frénay, Laurence Vénat-Bouvet, John L. Hopper, Mary B. Daly, Mary B. Terry, Esther M. John, Saundra S. Buys, Yosuf Yassin, Alexander Miron, David Goldgar, Christian F. Singer, Anne Catharina Dressler, Daphne Gschwantler-Kaulich, Georg Pfeiler, Thomas v. O. Hansen, Lars Jønson, Bjarni A. Agnarsson, Tomas Kirchhoff, Kenneth Offit, Vincent Devlin, Ana Dutra-Clarke, Marion Piedmonte, Gustavo C. Rodriguez, Katie Wakeley, John F. Boggess, Jack Basil, Peter E. Schwartz, Stephanie V. Blank, Amanda Ewart Toland, Marco Montagna, Cinzia Casella, Evgeny Imyanitov, Laima Tihomirova, Ignacio Blanco, Conxi Lazaro, Susan J. Ramus, Lara Sucheston, Beth Y. Karlan, Jenny Gross, Rita Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Magdalena Lochmann, Norbert Arnold, Simone Heidemann, Raymonda Varon-Mateeva, Dieter Niederacher, Christian Sutter, Helmut Deissler, Dorothea Gadzicki, Sabine Preisler-Adams, Karin Kast, Ines Schönbuchner, Trinidad Caldes, Miguel de La Hoya, Kristiina Aittomäki, Heli Nevanlinna, Jacques Simard, Amanda B. Spurdle, Helene Holland, Xiaoqing Chen, Radka Platte, Georgia Chenevix-Trench, Douglas F. Easton

Date Published: 6th Dec 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

INTRODUCTION Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of …f large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies. METHODS We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers. RESULTS SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P \textless 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r^2 = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, P(trend) = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, P(trend) = 0.018). CONCLUSIONS This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations.

Authors: Logan C. Walker, Zachary S. Fredericksen, Xianshu Wang, Robert Tarrell, Vernon S. Pankratz, Noralane M. Lindor, Jonathan Beesley, Sue Healey, Xiaoqing Chen, Dominique Stoppa-Lyonnet, Carole Tirapo, Sophie Giraud, Sylvie Mazoyer, Danièle Muller, Jean-Pierre Fricker, Capucine Delnatte, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Ines Schönbuchner, Helmut Deissler, Alfons Meindl, Frans B. Hogervorst, Martijn Verheus, Maartje J. Hooning, Ans Mw van den Ouweland, Marcel R. Nelen, Margreet Gem Ausems, Cora M. Aalfs, Christi J. van Asperen, Peter Devilee, Monique M. Gerrits, Quinten Waisfisz, Csilla I. Szabo, Douglas F. Easton, Susan Peock, Margaret Cook, Clare T. Oliver, Debra Frost, Patricia Harrington, D. Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Carol Chu, Rosemarie Davidson, Diana Eccles, Kai-Ren Ong, Jackie Cook, Tim Rebbeck, Katherine L. Nathanson, Susan M. Domchek, Christian F. Singer, Daphne Gschwantler-Kaulich, Anne-Catharina Dressler, Georg Pfeiler, Andrew K. Godwin, Tuomas Heikkinen, Heli Nevanlinna, Bjarni A. Agnarsson, Maria Adelaide Caligo, Håkan Olsson, Ulf Kristoffersson, Annelie Liljegren, Brita Arver, Per Karlsson, Beatrice Melin, Olga M. Sinilnikova, Lesley McGuffog, Antonis C. Antoniou, Georgia Chenevix-Trench, Amanda B. Spurdle, Fergus J. Couch

Date Published: 1st Dec 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying …g the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population. METHODS To evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). RESULTS The minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85; 95% CI, 0.76-0.97; P(trend) = 0.011) and ovarian cancer (per-allele HR, 0.69; 95% CI, 0.53-0.89; P(trend) = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers. CONCLUSIONS CASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers. IMPACT The combined application of these and other recently identified genetic risk modifiers could in the future allow better individual risk calculation and could aid in the individualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers.

Authors: Christoph Engel, Beatrix Versmold, Barbara Wappenschmidt, Jacques Simard, Douglas F. Easton, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Rebecca Mayes, D. Gareth Evans, Rosalind Eeles, Joan Paterson, Carole Brewer, Lesley McGuffog, Antonis C. Antoniou, Dominique Stoppa-Lyonnet, Olga M. Sinilnikova, Laure Barjhoux, Marc Frenay, Cécile Michel, Dominique Leroux, Helene Dreyfus, Christine Toulas, Laurence Gladieff, Nancy Uhrhammer, Yves-Jean Bignon, Alfons Meindl, Norbert Arnold, Raymonda Varon-Mateeva, Dieter Niederacher, Sabine Preisler-Adams, Karin Kast, Helmut Deissler, Christian Sutter, Dorothea Gadzicki, Georgia Chenevix-Trench, Amanda B. Spurdle, Xiaoqing Chen, Jonathan Beesley, Håkan Olsson, Ulf Kristoffersson, Hans Ehrencrona, Annelie Liljegren, Rob B. van der Luijt, Theo A. van Os, Flora E. van Leeuwen, Susan M. Domchek, Timothy R. Rebbeck, Katherine L. Nathanson, Ana Osorio, Teresa Ramón y Cajal, Irene Konstantopoulou, Javier Benítez, Eitan Friedman, Bella Kaufman, Yael Laitman, Phuong L. Mai, Mark H. Greene, Heli Nevanlinna, Kristiina Aittomäki, Csilla I. Szabo, Trinidad Caldes, Fergus J. Couch, Irene L. Andrulis, Andrew K. Godwin, Ute Hamann, Rita K. Schmutzler

Date Published: 8th Nov 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Screening in women at elevated risk for breast cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract

Not specified

Authors: Rita Katharina Schmutzler, Christoph Engel, Ingrid Schreer

Date Published: 20th Oct 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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