Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers

Susan L Neuhausen ,Nadine Tung,Sean Brummel,Georg Pfeiler,Yuan Chun Ding,Claudine Isaacs,Henry T Lynch ,Judy E Garber ,Wendy S Rubinstein ,Olufunmilayo I Olopade ,Katherine L Nathanson ,Patricia A Ganz ,Timothy R Rebbeck ,Christian F Singer ,Gail E Tomlinson ,Fergus J Couch ,Andrew K Godwin ,Joanne L Blum ,Mary B Daly ,Steven A Narod ,Jeffrey N Weitzel ,Daniel L Gillen

doi:10.1186/bcr2414

Abstract

IntroductionWomen who carry mutations in BRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared with the general population. However, risk estimates range from 20 to 80%, suggesting the presence of genetic and/or environmental risk modifiers. Based on extensive in vivo and in vitro studies, one important pathway for breast cancer pathogenesis may be the insulin-like growth factor (IGF) signaling pathway, which regulates both cellular proliferation and apoptosis. BRCA1 has been shown to directly interact with IGF signaling such that variants in this pathway may modify risk of cancer in women carrying BRCA mutations. In this study, we investigate the association of variants in genes involved in IGF signaling and risk of breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations.MethodsA cohort of 1,665 adult, female mutation carriers, including 1,122 BRCA1 carriers (433 cases) and 543 BRCA2 carriers (238 cases) were genotyped for SNPs in IGF1, IGF1 receptor (IGF1R), IGF1 binding protein (IGFBP1, IGFBP2, IGFBP5), and IGF receptor substrate 1 (IRS1). Cox proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was assumed; and for single SNP analyses, no additivity assumptions were made.ResultsAmong BRCA1 carriers, significant associations were found between risk of breast cancer and LD blocks in IGF1R (global P = 0.011 for LD block 2 and global P = 0.012 for LD block 11). Among BRCA2 carriers, an LD block in IGFBP2 (global P = 0.0145) was found to be associated with the time to breast cancer diagnosis. No significant LD block associations were found for the other investigated genes among BRCA1 and BRCA2 carriers.ConclusionsThis is the first study to investigate the role of genetic variation in IGF signaling and breast cancer risk in women carrying deleterious mutations in BRCA1 and BRCA2. We identified significant associations in variants in IGF1R and IRS1 in BRCA1 carriers and in IGFBP2 in BRCA2 carriers. Although there is known to be interaction of BRCA1 and IGF signaling, further replication and identification of causal mechanisms are needed to better understand these associations.

Highlights

Introduction Women who carry mutations inBRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared with the general population
No significant linkage disequilibrium (LD) block associations were found for the other investigated genes among BRCA1 and BRCA2 carriers. This is the first study to investigate the role of genetic variation in insulin-like growth factor (IGF) signaling and breast cancer risk in women carrying deleterious mutations in BRCA1 and BRCA2
We identified significant associations in variants in insulin-like growth factor-1 receptor (IGF1R) and insulin-like growth factor receptor substrate 1 (IRS1) in BRCA1 carriers and in IGFBP2 in BRCA2 carriers

Summary

Introduction

Introduction Women who carry mutations inBRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared with the general population. Among BRCA1 and BRCA2 mutation carriers, there is considerable variability in both the age at diagnosis and the incidence of breast and ovarian cancers, even among women who carry the same BRCA1 and BRCA2 mutation [6,7,8] These risk estimates show that such women are at extremely high risk for developing breast cancer, and illustrate that there is great variability in the time to breast cancer diagnosis among carriers. These observations are consistent with the hypothesis that the breast cancer risk in mutation carriers is modified by other genetic and/or environmental factors. There are published reports of genetic modifiers of cancer risk in mutation carriers (for example, variants in AIB1 in BRCA1; variants in RAD51, FGFR2 and MAP3K1 in BRCA2; and variants in TNRC9 in BRCA1 and BRCA2) [9,10,11,12,13]

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