Article

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

Yuan C Ding, Lesley McGuffog, Sue Healey, Eitan Friedman, Yael Laitman, Shani- Paluch-Shimon, Bella Kaufman, 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, 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, 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, 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, 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, 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

Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
Cancer Epidemiology Biomarkers &amp Prevention (impact factor: 4.12). 06/2012; 21(8):1362-70. DOI:10.1158/1055-9965.EPI-12-0229 pp.1362-70
Source: PubMed

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

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Keywords

95% confidence interval
 
affects insulin-like growth factor
 
BRCA1 carriers
 
BRCA1 mutation carriers
 
BRCA1 mutations
 
BRCA2 mutation carriers
 
breast cancer risk
 
class II HR
 
class II mutations
 
insulin receptor substrate 1
 
IRS1
 
IRS1 Gly972Arg single-nucleotide polymorphism
 
IRS1 variants
 
modifies ovarian cancer risk
 
mutation class
 
ovarian cancer risk
 
ovarian cancer risks
 
ovarian cancers
 
retrospective cohort approach modeling
 
significant associations