A non-synonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers

Introduction

Women who carry mutations in BRCA1 or BRCA2 are at a substantially increased risk of developing breast and/or ovarian cancers. Lifetime risks for breast cancer range from 40–87% and for ovarian cancer from 11–68% (1, 2). In addition to variability in the incidence of breast and ovarian cancers, there is also variability in age at diagnosis and type of cancer in the index case (proband) (1), even among women who carry the same BRCA mutation (3) and among women in the same family (4). These observations suggest that cancer risk in mutation carriers is modified by other genetic and/or environmental factors.

IRS1 is a docking protein for both the insulin-like growth factor receptor 1 (IGF1R) and the insulin receptor (IR), and as such is central to a network of intracellular signaling molecules (5)........

Methods

Subjects: BRCA1 and BRCA2 mutation carriers

Carriers of pathogenic mutations in BRCA1 and BRCA2 are from one of 36 centers from North America, Europe, the Mediterranean, and Australia participating in CIMBA (13).
The participants were all enrolled under IRB-approved protocols at the respective institutions, and all signed informed consent. Inclusion criteria for this analysis were female carriers of pathogenic BRCA1 or BRCA2 mutations who were 18 years or older at recruitment and were of self-reported non-Hispanic white Caucasian ancestry. Information collected included year of birth, mutation type including nucleotide position and base change, age at last follow-up, age at breast and/or ovarian cancer diagnosis, and age or date at bilateral prophylactic mastectomy or oophorectomy. Characteristics of the mutations carriers are shown in the Supplemental Table.....