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A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers

2012; American Association for Cancer Research; Volume: 21; Issue: 8 Linguagem: Inglês

10.1158/1055-9965.epi-12-0229

1538-7755

Yuan Chun 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 Lubiński, Katarzyna Jaworska, Katarzyna Durda, Jacek Gronwald, Tomasz Huzarski, Cezary Cybulski, Tomasz Byrski, Ana Osório, Teresa Ramóny Cajal, Alexandra Stavropoulou, Javier Benı́tez, Ute Hamann, Matti A. Rookus, Cora M. Aalfs, Judith L. de Lange, Hanne Meijers‐Heijboer, Jan C. Oosterwijk, Christi J. van Asperen, E. Gómez, 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, Rosalind A. Eeles, Julian Adlard, Rosemarie Davidson, Diana Eccles, Trevor Cole, Jackie Cook, Carole Brewer, Marc Tischkowitz, Andrew K. Godwin, Harsh B. 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 B. Daly, Alex Miron, Mary Beth Terry, Wendy K. Chung, Esther M. John, Melissa C. Southey, David E. Goldgar, Christian F. Singer, Muy-Kheng M. Tea, Daphne Gschwantler‐Kaulich, A. Fink-Retter, Thomas van Overeem Hansen, Bent Ejlertsen, Oskar T. Johannsson, Kenneth Offit, Kara Sarrel, Mia M. Gaudet, Joseph Vijai, Mark E. Robson, Marion Piedmonte, Lesley Andrews, David E. Cohn, Leslie R. DeMars, Paul DiSilvestro, Gustavo C. Rodriguez, Amanda E. Toland, Marco Montagna, Simona Agata, Evgeny Imyanitov, Claudine Isaacs, Ramūnas Janavičius, Conxi Lázaro, Ignacio Blanco, Susan J. Ramus, Lara Sucheston, Beth Y. Karlan, Jenny Gross, Patricia A. Ganz, Mary Beattie, Rita K. Schmutzler, Barbara Wappenschmidt, Alfons Meindl, Norbert Arnold, Dieter Niederacher, Sabine Preisler-Adams, D Gadzicki, Raymonda Varon-Mateeva, Helmut Deißler, Andrea Gehrig, Christian Sutter, Karin Kast, Heli Nevanlinna, Kristiina Aittomäki, Jacques Simard, Amanda B. Spurdle, Jonathan Beesley, Xiaohong Chen, Gail E. Tomlinson, Jeffrey N. Weitzel, Judy E. Garber, Olufunmilayo I. Olopade, Wendy S. Rubinstein, Nadine Tung, Joanne L. Blum, Steven A. Narod, Sean S. Brummel, Daniel L. Gillen, Noralane M. Lindor, Zachary Fredericksen, V. Shane Pankratz, Fergus J. Couch, Paolo Radice, Paolo Peterlongo, Mark H. Greene, Jennifer T. Loud, L. Phuong, Irene L. Andrulis, Gord Glendon, Hilmi Özçelik, 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,

Genetic factors in colorectal cancer

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; 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.