TY - JOUR
T1 - A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers
AU - SWE-BRCA
AU - Ding, Yuan C
AU - McGuffog, Lesley
AU - Healey, Sue
AU - Friedman, Eitan
AU - Laitman, Yael
AU - Paluch-Shimon, Shani-
AU - Kaufman, Bella
AU - Liljegren, Annelie
AU - Lindblom, Annika
AU - Olsson, Håkan
AU - Kristoffersson, Ulf
AU - Stenmark-Askmalm, Marie
AU - Melin, Beatrice
AU - Domchek, Susan M
AU - Nathanson, Katherine L
AU - Rebbeck, Timothy R
AU - Jakubowska, Anna
AU - Lubinski, Jan
AU - Jaworska, Katarzyna
AU - Durda, Katarzyna
AU - Gronwald, Jacek
AU - Huzarski, Tomasz
AU - Cybulski, Cezary
AU - Byrski, Tomasz
AU - Osorio, Ana
AU - Cajal, Teresa Ramóny
AU - Stavropoulou, Alexandra V
AU - Benítez, Javier
AU - Hamann, Ute
AU - Rookus, Matti
AU - Aalfs, Cora M
AU - de Lange, Judith L
AU - Meijers-Heijboer, Hanne E J
AU - Oosterwijk, Jan C
AU - van Asperen, Christi J
AU - Gómez García, Encarna B
AU - Hoogerbrugge, Nicoline
AU - Jager, Agnes
AU - van der Luijt, Rob B
AU - Easton, Douglas F
AU - Peock, Susan
AU - Frost, Debra
AU - Ellis, Steve D
AU - Platte, Radka
AU - Fineberg, Elena
AU - Evans, D Gareth
AU - Lalloo, Fiona
AU - Izatt, Louise
AU - Tischkowitz, Marc
AU - Hansen, Thomas V O
N1 - ©2012 AACR.
PY - 2012/8
Y1 - 2012/8
N2 - 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.
AB - 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.
KW - Breast Neoplasms/genetics
KW - Cohort Studies
KW - Female
KW - Genes, BRCA1
KW - Genes, BRCA2
KW - Genetic Predisposition to Disease
KW - Genotype
KW - Humans
KW - Insulin Receptor Substrate Proteins/genetics
KW - Mutation
KW - Ovarian Neoplasms/genetics
KW - Polymorphism, Single Nucleotide
U2 - 10.1158/1055-9965.EPI-12-0229
DO - 10.1158/1055-9965.EPI-12-0229
M3 - Article
C2 - 22729394
SN - 1055-9965
VL - 21
SP - 1362
EP - 1370
JO - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
JF - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
IS - 8
ER -