Common genomic variants are associated with incidence and clinicopathogenic features in familial breast cancer.

Objectives: Large-scale genome-wide association studies (GWAS) have identified more than 70 common genomic variants associated with breast cancer. It is estimated that these variants account for ~28% of the familial risk of breast cancer. We assessed the association of recently described variants with breast cancer cases from high-risk breast and/or ovarian cancer families. In addition, we investigated the association of these variants with clinicopathogenic features, including hormonal status and grade of tumour differentiation within our highly characterized cohort. Method(s): We examined 1136 female index cases from the Australian Victorian familial breast and ovarian cancer cohort. All individuals were assessed as high-risk through genetic testing services and had completed genetic screening for BRCA1 and BRCA2 mutations. High throughput genotyping was performed using the Fluidigm system for 62 common variants identified in GWAS (success rate > 0.95). Control genotype data was obtained from an Australian population-based control group (n = 711). Detailed breast cancer pathology was reviewed for 400 of the cases. Result(s): Individual associations in the familial setting were stronger compared to previous breast cancer GWAS. A significantly higher number of risk variants were found among women who did not harbour a BRCA1 or BRCA2 mutation when compared to population controls (p = 1.35x10-39) and those who did harbour a BRCA mutation (p = 0.0004). Women in the top quartile based on the number of risk variants had an average relative risk of 2.3. Many of the variants showed significant associations with hormone status and grade. Conclusion(s): Resultsofthisstudyconfirmtheimportantcontributionofcommonvariants to the incidence of breast cancer in the familial setting. The data indicate a direction for further research to determine if these associations can be used to help understand tumour heterogeneity and lead to improved treatment and prevention for high-risk brea