Genetic Variants May Modify Risk for Breast Cancer

While BRCA2 mutations are rare, the zinc finger protein (ZNF365) variant is more common, and is seen in one in ten individuals.

An international study led by scientists at Memorial Sloan-Kettering Cancer Center, (MSKCC; New York, NY, USA), analyzed DNA samples from 6,272 women with BRCA2 mutations in a two-stage genome-wide association study. The chromosome 10 variant identified in the study, near the gene ZNF365, decreased the risk of breast cancer by approximately 25% in women also carrying a mutation of the BRCA2 gene. In addition, the team found that other variants, including fibroblast growth factor receptor 2 (FGFR2), recognized to increase breast cancer risk in the general population, also served as risk modifiers for women with BRCA2 mutations.

The major finding of the study is that only those loci known to be associated with breast cancer risk in the general population; including FGFR2 (rs2981575) modified BRCA2-associated risk in our high-risk population. Two novel loci, on chromosomes 10 in ZNF365 (rs16917302) and chromosome 20 (rs311499), were shown to modify risk in BRCA2 mutation carriers, although not at a genome-wide level of significance.

Kenneth Offit, M.D., M.P.H., Chief of the Clinical Genetics Service at MSKCC, said, "The risk of breast cancer associated with BRCA2 mutations varies widely. Our goal in this study was to test the hypothesis that common genetic variants may modify cancer risk in those already carrying 'high risk' mutations." He added, "It is interesting that our study of BRCA2 and a companion study of BRCA1 both found that women with BRCA mutations likely have the same risk modifiers for breast cancer as women in the general population." The study was published online on October 28, 2010, in PLoS Genetics.

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Memorial Sloan-Kettering Cancer Center