Cancer Epidemiology Biomarkers & Prevention: A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers

Published On: August 1, 2012
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Yuan C Ding 1, Lesley McGuffog, Sue Healey, Eitan Friedman, Yael Laitman, Shani- Paluch-Shimon, Bella Kaufman, SWE-BRCA; Annelie Liljegren, Annika Lindblom, Håkan Olsson, Ulf Kristoffersson, Marie Stenmark-Askmalm, Beatrice Melin, Susan M Domchek, Katherine L Nathanson, Timothy R Rebbeck, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska, Katarzyna Durda, Jacek Gronwald, Tomasz Huzarski, Cezary Cybulski, Tomasz Byrski, Ana Osorio, Teresa Ramóny Cajal, Alexandra V Stavropoulou, Javier Benítez, Ute Hamann, HEBON; Matti Rookus, Cora M Aalfs, Judith L de Lange, Hanne E J Meijers-Heijboer, Jan C Oosterwijk, Christi J van Asperen, Encarna B Gómez García, Nicoline Hoogerbrugge, Agnes Jager, Rob B van der Luijt, EMBRACE; Douglas F Easton, Susan Peock, Debra Frost, Steve D Ellis, Radka Platte, Elena Fineberg, D Gareth Evans, Fiona Lalloo, Louise Izatt, Ros Eeles, Julian Adlard, Rosemarie Davidson, Diana Eccles, Trevor Cole, Jackie Cook, Carole Brewer, Marc Tischkowitz, Andrew K Godwin, Harsh Pathak, GEMO Study Collaborators; Dominique Stoppa-Lyonnet, Olga M Sinilnikova, Sylvie Mazoyer, Laure Barjhoux, Mélanie Léoné, Marion Gauthier-Villars, Virginie Caux-Moncoutier, Antoine de Pauw, Agnès Hardouin, Pascaline Berthet, Hélène Dreyfus, Sandra Fert Ferrer, Marie-Agnès Collonge-Rame, Johanna Sokolowska, Saundra Buys, Mary Daly, Alex Miron, Mary Beth Terry, Wendy Chung, Esther M John, Melissa Southey, David Goldgar, Christian F Singer, Muy-Kheng Maria Tea, Daphne Gschwantler-Kaulich, Anneliese Fink-Retter, Thomas V O Hansen, Bent Ejlertsen, Oskar T Johannsson, Kenneth Offit, Kara Sarrel, Mia M Gaudet, Joseph Vijai, Mark Robson, Marion R Piedmonte, Lesley Andrews, David Cohn, Leslie R DeMars, Paul DiSilvestro, Gustavo Rodriguez, Amanda Ewart Toland, Marco Montagna, Simona Agata, Evgeny Imyanitov, Claudine Isaacs, Ramunas Janavicius, Conxi Lazaro, Ignacio Blanco, Susan J Ramus, Lara Sucheston, Beth Y Karlan, Jenny Gross, Patricia A Ganz, Mary S Beattie, Rita K 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, KConFab Investigators; Amanda B Spurdle, Jonathan Beesley, Xiaoqing Chen, Gail E Tomlinson, Jeffrey Weitzel, Judy E Garber, Olufunmilayo I Olopade, Wendy S Rubinstein, Nadine Tung, Joanne L Blum, Steven A Narod, Sean Brummel, Daniel L Gillen, Noralane Lindor, Zachary Fredericksen, Vernon S Pankratz, Fergus J Couch, Paolo Radice, Paolo Peterlongo, Mark H Greene, Jennifer T Loud, Phuong L Mai, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, OCGN; Anne-Marie Gerdes, Mads Thomassen, Uffe Birk Jensen, Anne-Bine Skytte, Maria A Caligo, Andrew Lee, Georgia Chenevix-Trench, Antonis C Antoniou, Susan L Neuhausen, Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

Erratum in

  • Cancer Epidemiol Biomarkers Prev. 2012 Dec;21(12):2278

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).

Conclusion: 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.

Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.

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