Funding Agencies|NIH|R01CA74415P30CA033752|Israel cancer association||Mutua Madrilena Foundation||Red de Investigacion en Cancer|RD06/0020/1160|Spanish Ministry of Science and Innovation|FIS P1081120SAF2010-20493|Cancer Research UK|C1287/A10118C1287/A11990C5047/A8385|NIHR||NEYE Foundation||Clinical Genetics Branch, DCEG National Cancer Institute (NCI)||Community Oncology and Prevention Trials Program-COPTRG National Cancer Institute (NCI)||Russian Foundation for Basic Research|10-04-9211010-04-9260111-04-00227|Federal Agency for Science and Innovations|02.740.11.0780|Royal Society|JP090615|Research Council of Lithuania|LIG-19/2010|Institut Catala dOncologia (ICO)||Asociacion Espanola Contra el Cancer, Spanish Health Research Fund||Carlos III Health Institute||Catalan Health Institute||Autonomous Government of Catalonia|ISCIIIRETIC RD06/0020/1051PI10/01422PI10/314882009SGR290|American Cancer Society|120950-SIOP-06-258-06-COUN|German Cancer Aid|DKH 109076|Helsinki University Central Hospital||Academy of Finland|132473|Finnish Cancer Society||Sigrid Juselius Foundation||Canadian Institutes of Health Research||Canadian Breast Cancer Research Alliance|019511|NCI, under RFA|CA-06-503|Cancer Care Ontario|U01 CA69467|Cancer Prevention Institute of California|U01 CA69417|Columbia University|U01 CA69398|Fox Chase Cancer Center|U01 CA69631|Huntsman Cancer Institute|U01 CA69446|University of Melbourne|U01 CA69638|National Health and Medical Research Council of Australia||New South Wales Cancer Council||Victorian Health Promotion Foundation (Australia)||Victorian Breast Cancer Research Consortium||NITA|P01 CA16094R01 CA22435|National Institutes of Health|P30 CA13696P30 ES009089UL1 RR025764R01278978|National Center for Research Resources||National Center for Advancing Translational Sciences||NCI|P30 CA042014|NHMRC|145684288704454508|US NCI at the NIH|NO2-CP-11019-50N02-CP-65504|Westat, Inc.||Breast cancer Research Foundation||Komen Foundation for the Cure||Dutch Cancer Society|NKI1998-1854NKI2004-3088NKI2007-3756|ZonMW|91109024|OSU Comprehensive Cancer Center|||R01-CA083855||R01-CA102776||R01CA140323||U01CA69631||5U01CA113916|
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.
McGuffog, LesleyUniversity of Cambridge Worts Causeway, England
(författare)
Healey, SueRoyal Brisbane Hospital, Australia
(författare)
Friedman, EitanChaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel
(författare)
Laitman, YaelChaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel
(författare)
Paluch-Shimon, Shani-Chaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel
(författare)
Kaufman, BellaChaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel
(författare)
Liljegren, AKarolinska University Hospital, Sweden,Department of Molecular Medicine and Surgery (MMK)(Swepub:ki)ea9fe46817296ecd90ed41b56a458374
(författare)
Lindblom, AKarolinska University Hospital, Sweden,Department of Molecular Medicine and Surgery (MMK)(Swepub:ki)b9f8f0548b7d664621e22fda4620354b
(författare)
Olsson, HåkanBreastcancer-genetics,Bröstcancer-genetik,University of Lund Hospital, Sweden
(författare)
Kristoffersson, UlfDivision of Clinical Genetics,Avdelningen för klinisk genetik,University of Lund Hospital, Sweden(Swepub:lu)81fb2efe-e4d0-4960-a27d-665b8b523a3c
(författare)
Domchek, Susan M.University of Penn, PA, USA,Ist Oncology Veneto IOV IRCCS, Italy
(författare)
Nathanson, Katherine L.University of Penn, PA, USA
(författare)
Rebbeck, Timothy R.University of Penn, PA, USA
(författare)
Jakubowska, AnnaPomeranian Medical University, Poland
(författare)
Lubinski, JanPomeranian Medical University, Poland
(författare)
Jaworska, KatarzynaPomeranian Medical University, Poland
(författare)
Durda, KatarzynaPomeranian Medical University, Poland
(författare)
Gronwald, JacekPomeranian Medical University, Poland
(författare)
Huzarski, TomaszPomeranian Medical University, Poland
(författare)
Antoniou, Antonis C.University of Pisa, Italy University Hospital Pisa, Italy,University of Cambridge Worts Causeway, England
(författare)
Byrski, TomaszPomeranian Medical University, Poland
(författare)
Osorio, AnaSpanish National Cancer Research Centre, Spain Spanish National Cancer Research Centre, Spain Spanish Network Rare Disease CIBERER, Spain
(författare)
Cajal, Teresa RamónyHospital Santa Creu and Sant Pau, Spain
(författare)
Stavropoulou, Alexandra V.National Centre Science Research Demokritos, Greece
(författare)
Benítez, JavierSpanish National Cancer Research Centre, Spain Spanish National Cancer Research Centre, Spain Spanish Network Rare Disease CIBERER, Spain
(författare)
Rookus, MattiNetherlands Cancer Institute, Netherlands
(författare)
Aalfs, Cora M.University of Amsterdam, Netherlands
(författare)
de Lange, Judith L.Netherlands Cancer Institute, Netherlands
(författare)
Meijers-Heijboer, Hanne E. J.Vrije University of Amsterdam Medical Centre, Netherlands,Cancer Prevent Institute Calif, CA, USA Stanford University, CA, USA Stanford Cancer Institute, CA, USA
(författare)
Oosterwijk, Jan C
(författare)
van Asperen, Christi J.Leiden University, Netherlands
(författare)
Garcia, Encarna B. GomezMUMC, Netherlands
(författare)
Hoogerbrugge, NicolineRadboud University of Nijmegen, Netherlands
(författare)