Breast cancer and DNA epair gene SNPs in a family cancer registry population

Abstract

10514 Background: Alterations in the DNA double-strand break repair (DSBR) pathway are associated with cancer risk. Mutations in the genes BRCA1/2 disrupt DNA DSBR. Variations in breast cancer penetrance among BRCA1/2 mutation carriers, and familial patterns among women without known BRCA1/2 mutations may be related to polymorphisms of genes in the DNA-DSBR pathway. Methods: Using a case-control study design with individuals in the UCLA Family Cancer Registry (FCR), we examined the independent effects of 100 SNPs in 19 DNA-DSBR genes. SNPs were assayed using the Applied Biosystems SNPlex™ assay. Results: 630 consecutive females from 508 families in the UCLA FCR selected for familial risk of breast cancer were included in the study. Table 1 describes select subject characteristics. Preliminary association analysis of the Caucasian subset using a nonparametric permutation method, which controls for Ashkenazi Jewish heritage and dependencies among relatives, suggests that polymorphisms within RAD21 (p=0.0044, p=0.0005), XRCC2 (p = 0.0069), XRCC4 (p =0.0511), and BRIP1 (p =0.0107) may be associated with a change in risk of breast cancer. Using only unrelated Caucasian subjects in a logistic regression analysis with covariates such as age, BMI, and Ashkenazi Jewish heritage, the effects of these polymorphisms remain significant, with 32% to 74% change in the odds of breast cancer. Conclusions: We have identified five potential SNPs in genes in the DNA-DSBR pathway that appear to be associated with a change in risk of breast cancer. This hypothesis generating study lends support to a role for polymorphisms of the DNA-repair pathway in breast carcinogenesis. Assessment of gene-environment and gene-gene interactions will help to elucidate carcinogenic mechanisms. Further validation in similar populations is warranted. (Funded by the Breast Cancer Research Foundation and NIH/NCI CA87949 R25 Career Development Program.) [Table: see text] No significant financial relationships to disclose.