A Nonsynonymous Polymorphism inIRS1Modifies Risk of Developing Breast and Ovarian Cancers inBRCA1and Ovarian Cancer inBRCA2Mutation Carriers
Authors: Ding Yuan C. , McGuffog Lesley , Healey Sue , Friedman Eitan , Laitman Yael , Paluch–Shimon Shani- , Kaufman Bella ,   for SWE-BRCA, Liljegren Annelie , Lindblom Annika , Olsson Håkan , Kristoffersson Ulf , Stenmark-Askmalm Marie , Melin Beatrice , Domchek Susan M. , Nathanson Katherine L. , Rebbeck Timothy R. , Jakubowska Anna , Lubinski Jan , Jaworska Katarzyna , Durda Katarzyna , Gronwald Jacek , Huzarski Tomasz , Cybulski Cezary , Byrski Tomasz , Osorio Ana , Cajal Teresa Ramóny , Stavropoulou Alexandra V. , Benítez Javier , Hamann Ute ,   for HEBON, Rookus Matti , Aalfs Cora M. , de Lange Judith L. , Meijers-Heijboer Hanne E.J. , Oosterwijk Jan C. , van Asperen Christi J. , Gómez García Encarna B. , Hoogerbrugge Nicoline , Jager Agnes , van der Luijt Rob B. ,   for EMBRACE, Easton Douglas F. , Peock Susan , Frost Debra , Ellis Steve D. , Platte Radka , Fineberg Elena , Evans D. Gareth , Lalloo Fiona , Izatt Louise , Eeles Ros , Adlard Julian , Davidson Rosemarie , Eccles Diana , Cole Trevor , Cook Jackie , Brewer Carole , Tischkowitz Marc , Godwin Andrew K. , Pathak Harsh ,   for GEMO Study Collaborators, Stoppa-Lyonnet Dominique , Sinilnikova Olga M. , Mazoyer Sylvie , Barjhoux Laure , Léoné Mélanie , Gauthier-Villars Marion , Caux-Moncoutier Virginie , de Pauw Antoine , Hardouin Agnès , Berthet Pascaline , Dreyfus Hélène , Ferrer Sandra Fert , Collonge-Rame Marie-Agnès , Sokolowska Johanna , Buys Saundra , Daly Mary , Miron Alex , Terry Mary Beth , Chung Wendy , John Esther M. , Southey Melissa , Goldgar David , Singer Christian F. , Tea Muy-Kheng Maria , Gschwantler-Kaulich Daphne , Fink-Retter Anneliese , Hansen Thomas V.O. , Ejlertsen Bent , Johannsson Oskar T. , Offit Kenneth , Sarrel Kara , Gaudet Mia M. , Vijai Joseph , Robson Mark , Piedmonte Marion R. , Andrews Lesley , Cohn David , DeMars Leslie R. , DiSilvestro Paul , Rodriguez Gustavo , Toland Amanda Ewart , Montagna Marco , Agata Simona , Imyanitov Evgeny , Isaacs Claudine , Janavicius Ramunas , Lazaro Conxi , Blanco Ignacio , Ramus Susan J. , Sucheston Lara , Karlan Beth Y. , Gross Jenny , Ganz Patricia A. , Beattie Mary S. , Schmutzler Rita K. , Wappenschmidt Barbara , Meindl Alfons , Arnold Norbert , Niederacher Dieter , Preisler-Adams Sabine , Gadzicki Dorotehea , Varon-Mateeva Raymonda , Deissler Helmut , Gehrig Andrea , Sutter Christian , Kast Karin , Nevanlinna Heli , Aittomäki Kristiina , Simard Jacques ,   for KConFab Investigators, Spurdle Amanda B. , Beesley Jonathan , Chen Xiaoqing , Tomlinson Gail E. , Weitzel Jeffrey , Garber Judy E. , Olopade Olufunmilayo I. , Rubinstein Wendy S. , Tung Nadine , Blum Joanne L. , Narod Steven A. , Brummel Sean , Gillen Daniel L. , Lindor Noralane , Fredericksen Zachary , Pankratz Vernon S. , Couch Fergus J. , Radice Paolo , Peterlongo Paolo , Greene Mark H. , Loud Jennifer T. , Mai Phuong L. , Andrulis Irene L. , Glendon Gord , Ozcelik Hilmi ,   for OCGN, Gerdes Anne-Marie , Thomassen Mads , Jensen Uffe Birk , Skytte Anne-Bine , Caligo Maria A. , Lee Andrew , Chenevix-Trench Georgia , Antoniou Antonis C. , Neuhausen Susan L. 
Published: August 2012

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; Pdifference, 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. Cancer Epidemiol Biomarkers Prev; 21(8); 1362–70. ©2012 AACR.