Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

Abstract

<p>The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic <em>BRCA1</em> or <em>BRCA2</em> variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 <em>BRCA1</em> and 10,740 <em>BRCA2</em> pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in <em>BRCA1</em> suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping <em>SULT1A1</em> suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in <em>BRCA1</em> pathogenic variant carriers. Functional analyses of <em>SULT1A1</em> showed that reduced mRNA expression in pathogenic <em>BRCA1</em> variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in <em>BRCA1</em> plus <em>SULT1A1</em> deletions contribute to variable breast cancer risk in <em>BRCA1</em> carriers.<br></p>