Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Commun Biol. 2022 Oct 6;5(1):1061. doi: 10.1038/s42003-022-03978-6.
The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 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 BRCA1 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 SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 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 BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.
胚系拷贝数变异 (CNVs) 对携带致病性 BRCA1 或 BRCA2 变异个体癌症风险的贡献相对未知。我们对 15342 名 BRCA1 和 10740 名 BRCA2 致病性变异携带者进行了全基因组范围内最大规模的 CNV 分析。我们使用这些结果优先选择候选乳腺癌风险修饰基因进行实验室分析和生物学验证。值得注意的是，与非 CNV 致病性变异相比，BRCA1 缺失的 HR 提示乳腺癌风险估计值升高（危险比 (HR) = 1.21，95%置信区间 (95% CI) = 1.09-1.35）。相比之下，BRCA1 致病性变异携带者中重叠 SULT1A1 的缺失提示乳腺癌风险降低（HR = 0.73，95% CI 0.59-0.91）。SULT1A1 的功能分析表明，致病性 BRCA1 变异细胞中 mRNA 表达降低与细胞增殖减少和 DNA 损伤后处理 DNA 损伤剂时的 DNA 损伤减少有关。这些数据提供了证据，表明 BRCA1 中的有害变异加上 SULT1A1 缺失导致 BRCA1 携带者的乳腺癌风险存在差异。
