A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers.

Journal: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology

Published: June 26, 2012

Abstract

Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.

Methods: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers.

Results: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03).

Conclusions: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. Conclusions: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.

Authors

Yuan Ding, Lesley Mcguffog, Sue Healey, Eitan Friedman, Yael Laitman, Shani- Paluch Shimon, Bella Kaufman, Annika Lindblom, Håkan Olsson, Ulf Kristoffersson, Marie Stenmark Askmalm, Beatrice Melin, Susan Domchek, Katherine Nathanson, Timothy Rebbeck, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska, Katarzyna Durda, Jacek Gronwald, Tomasz Huzarski, Cezary Cybulski, Tomasz Byrski, Ana Osorio, Teresa Cajal, Alexandra Stavropoulou, Javier Benítez, Ute Hamann, Matti Rookus, Judith De Lange, Hanne E Meijers Heijboer, Jan Oosterwijk, Christi Van Asperen, Encarna Gómez García, Nicoline Hoogerbrugge, Agnes Jager, Rob Van Der Luijt, Douglas Easton, Susan Peock, Steve Ellis, Radka Platte, Elena Fineberg, D Evans, Fiona Lalloo, Louise Izatt, Ros Eeles, Julian Adlard, Rosemarie Davidson, Diana Eccles, Trevor Cole, Jackie Cook, Carole Brewer, Marc Tischkowitz, Andrew Godwin, Harsh Pathak, Dominique Stoppa Lyonnet, Olga Sinilnikova, Sylvie Mazoyer, Mélanie Léoné, Marion Gauthier Villars, Virginie Caux Moncoutier, Antoine De Pauw, Agnès Hardouin, Pascaline Berthet, Hélène Dreyfus, Sandra Ferrer, Marie-agnès Collonge Rame, Johanna Sokolowska, Saundra Buys, Mary Daly, Alex Miron, Mary Terry, Wendy Chung, Esther John, Melissa Southey, David Goldgar, Christian Singer, Muy-kheng Tea, Daphne Gschwantler Kaulich, Anneliese Fink Retter, Thomas Hansen, Bent Ejlertsen, Oskar Johannsson, Kenneth Offit, Kara Sarrel, Mia Gaudet, Joseph Vijai, Mark Robson, Marion Piedmonte, Lesley Andrews, David Cohn, Leslie Demars, Paul Disilvestro, Gustavo Rodriguez, Amanda Toland, Marco Montagna, Simona Agata, Evgeny Imyanitov, Claudine Isaacs, Ramunas Janavicius, Conxi Lazaro, Ignacio Blanco, Susan Ramus, Lara Sucheston, Beth Karlan, Jenny Gross, Patricia Ganz, Mary Beattie, Rita Schmutzler, Barbara Wappenschmidt, Alfons Meindl, Norbert Arnold, Dieter Niederacher, Sabine Preisler Adams, Dorotehea Gadzicki, Raymonda Varon Mateeva, Helmut Deissler, Andrea Gehrig, Christian Sutter, Karin Kast, Heli Nevanlinna, Kristiina Aittomäki, Jacques Simard, Amanda Spurdle, Jonathan Beesley, Xiaoqing Chen, Gail Tomlinson, Judy Garber, Olufunmilayo Olopade, Wendy Rubinstein, Nadine Tung, Joanne Blum, Steven Narod, Sean Brummel, Daniel Gillen, Noralane Lindor, Zachary Fredericksen, Vernon Pankratz, Fergus Couch, Paolo Radice, Paolo Peterlongo, Mark Greene, Jennifer Loud, Phuong Mai, Irene Andrulis, Gord Glendon, Hilmi Ozcelik, Anne-marie Gerdes, Mads Thomassen, Uffe Jensen, Anne-bine Skytte, Maria Caligo, Georgia Chenevix Trench, Antonis Antoniou, Susan Neuhausen

Relevant Conditions

Breast Cancer, Ovarian Cancer

A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers.

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