A Nonsynonymous Polymorphism inIRS1Modifies Risk of Developing Breast and Ovarian Cancers inBRCA1and Ovarian Cancer inBRCA2Mutation Carriers

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 [Hazard ratio (HR) = 1.43; 95% 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 2 mutations than class 1 (mutations (class 2 HR=1.86, 95% CI: 1.28–2.70; class 1 HR=0.86, 95%CI:0.69–1.09; p-for difference=0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class 2 mutation carriers (HR = 2.42; p = 0.03). Conclusion The IRS1 Gly972Arg SNP, 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 2 mutation carriers. Impact These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.

BRCA1 and BRCA2 5′ noncoding region variants identified in breast cancer patients alter promoter activity and protein binding

“…Low‐risk variants, largely identified by genome‐wide association studies, are usually common and cause subtle functional effects, such as small but significant changes in gene expression due to altered activity of proximal and distal regulatory elements (reviewed in Bogdanova, Helbig, & Dork, ; Ghoussaini, Pharoah, & Easton, ; Skol, Sasaki, & Onel, ). Evidence suggests that combinations of low, moderate, and high‐risk variants could confer a clinically significant risk of disease (Ding et al., ; Kuchenbaecker et al., ; Sawyer et al., ). Identification and evaluation of all such variants is therefore crucial for accurately predicting BC risk.…”

Novel insulin receptor substrate 1 and 2 variants in breast and colorectal cancer

“…In vivo overexpression of IRS-1 and IRS-2 in the mammary gland of murine models was found to cause mammary tumorigenesis and metastasis (35), suggesting that IRS-1 and IRS-2 behave as oncogenes in vivo . The Gly972Arg IRS-1 polymorphism has been associated with increased BC risk for BRCA1 class II mutation carriers (10). In the present study, mutational analysis of IRS in BC and CRC identified several variants with pathogenic potential.…”

“…Moreover, IRS-1 G972R significantly modifies the risk of developing ovarian cancer in BRCA1 and BRCA2 mutation carriers (10). Our previous results suggest that IRS-1 may influence adenoma formation, CRC progression and liver metastasis (11).…”

Breast cancer risk for Korean women with germline mutations in BRCA1 and BRCA2

“…Consistent with this, studies of the relatives of populationbased or hospital-based cases selected regardless of a family history have found lower estimates of penetrance to age 70 years, less than 60 % for breast cancer risk for BRCA1 mutation carriers and 30-56 % for BRCA2 mutation carriers [6,[8][9][10][11][12]. In addition, some studies have found evidence that risk varies by specific mutations [13,14], other genetic modifiers [15][16][17], birth cohort [18,19], and reproductive and lifestyle factors [20,21].…”