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Title: A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers.
Authors: Ding YC,  McGuffog L,  Healey S,  Friedman E,  Laitman Y,  Paluch-Shimon S,  Kaufman B,  SWE-BRCA,  Liljegren A,  Lindblom A,  Olsson H,  Kristoffersson U,  Stenmark-Askmalm M,  Melin B,  Domchek SM,  Nathanson KL,  Rebbeck TR,  Jakubowska A,  Lubinski J,  Jaworska K,  Durda K,  Gronwald J,  Huzarski T,  Cybulski C,  Byrski T,  Osorio A,  Cajal TR,  Stavropoulou AV,  Benítez J,  Hamann U,  HEBON,  Rookus M,  Aalfs CM,  de Lange JL,  Meijers-Heijboer HE,  Oosterwijk JC,  van Asperen CJ,  Gómez García EB,  Hoogerbrugge N,  Jager A,  van der Luijt RB,  EMBRACE,  Easton DF,  Peock S,  Frost D,  Ellis SD,  Platte R,  Fineberg E,  Evans DG,  Lalloo F,  Izatt L,  Eeles R,  Adlard J,  Davidson R,  Eccles D,  Cole T,  Cook J,  Brewer C,  Tischkowitz M,  Godwin AK,  Pathak H,  GEMO Study Collaborators,  Stoppa-Lyonnet D,  Sinilnikova OM,  Mazoyer S,  Barjhoux L,  Léoné M,  Gauthier-Villars M,  Caux-Moncoutier V,  de Pauw A,  Hardouin A,  Berthet P,  Dreyfus H,  Ferrer SF,  Collonge-Rame MA,  Sokolowska J,  Buys S,  Daly M,  Miron A,  Terry MB,  Chung W,  John EM,  Southey M,  Goldgar D,  Singer CF,  Tea MK,  Gschwantler-Kaulich D,  Fink-Retter A,  Hansen TV,  Ejlertsen B,  Johannsson OT,  Offit K,  Sarrel K,  Gaudet MM,  Vijai J,  Robson M,  Piedmonte MR,  Andrews L,  Cohn D,  DeMars LR,  DiSilvestro P,  Rodriguez G,  Toland AE,  Montagna M,  Agata S,  Imyanitov E,  Isaacs C,  Janavicius R,  Lazaro C,  Blanco I,  Ramus SJ,  Sucheston L,  Karlan BY,  Gross J,  Ganz PA,  Beattie MS,  Schmutzler RK,  Wappenschmidt B,  Meindl A,  Arnold N,  Niederacher D,  Preisler-Adams S,  Gadzicki D,  Varon-Mateeva R,  Deissler H,  Gehrig A,  Sutter C,  Kast K,  Nevanlinna H,  Aittomäki K,  Simard J,  KConFab Investigators,  Spurdle AB,  Beesley J,  Chen X,  Tomlinson GE,  Weitzel J,  Garber JE,  Olopade OI,  Rubinstein WS,  Tung N,  Blum JL,  Narod SA,  Brummel S,  Gillen DL,  Lindor N,  Fredericksen Z,  Pankratz VS,  Couch FJ,  Radice P,  Peterlongo P,  Greene MH,  Loud JT,  Mai PL,  Andrulis IL,  Glendon G,  Ozcelik H,  OCGN,  Gerdes AM,  Thomassen M,  Jensen UB,  Skytte AB,  Caligo MA,  Lee A,  Chenevix-Trench G,  Antoniou AC,  Neuhausen SL,  Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)
Journal: Cancer Epidemiol Biomarkers Prev
Date: 2012 Aug
Branches: CGB
PubMed ID: 22729394
PMC ID: PMC3415567
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.