Exome sequencing reveals a high prevalence of BRCA1 and BRCA2 founder variants in a diverse population-based biobank
Exome sequencing reveals a high prevalence of BRCA1 and BRCA2 founder variants in a diverse population-based biobank
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DOI：
10.1186/s13073-019-0691-1
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发表时间：
2019-12-31
期刊：
影响因子：
12.3
通讯作者：
Kenny, Eimear E.
中科院分区：
文献类型：
--
作者：
Abul-Husn, Noura S.;Soper, Emily R.;Kenny, Eimear E.
BRCA 1和BRCA 2（BRCA 1/2）的致病性变异导致乳腺癌、卵巢癌和其他癌症的风险增加，但一般人群中大多数变异阳性个体并不知道其风险，而且对非欧洲人群的患病率知之甚少。我们在纽约市的电子健康记录（EHR）相关BioMe生物库中调查了BRCA 1/2的患病率和影响。方法对来自30,223名成人BioMe参与者的外显子组序列数据进行BRCA 1/2致病性变异的评估。患病率估计是在遗传祖先和自我报告定义的人群中进行的。EHR数据用于评估变异阳性个体的临床特征。结果有218例（0.7%）携带预期的致病性变异，导致总患病率为1/139。患病率最高的是德系犹太人（AJ; 1/49），菲律宾和其他东南亚人（1/81）和非AJ欧洲人（1/103）血统的个体。在218名变异阳性个体中，112名（51.4%）携带已知的创始人变异：80名具有AJ创始人变异（BRCA 1 c.5266dupC和c.68_69delAG，以及BRCA 2 c.5946delT），8名具有波多黎各创始人变异（BRCA 2 c.3922G>T），24名具有19种其他创始人变异之一。非欧洲人群更有可能携带ClinVar中未分类的BRCA 1/2变异体或具有不确定或相互矛盾的致病性证据（不确定/相互矛盾）。在混合血统人群中，例如来自非洲，欧洲和美洲的遗传血统的西班牙裔/拉丁美洲人，非洲遗传血统的比例与隐藏不确定/冲突变体的可能性之间存在很强的相关性。大约28%的变异阳性个体有BRCA 1/2相关癌症的个人史，45%有BRCA 1/2相关癌症的个人或家族史。大约27%的变异阳性个体先前进行过BRCA 1/2的临床基因检测。然而，具有AJ创始者变异的个体进行临床测试的可能性（39%）是具有其他致病性变异的个体（20%）的两倍。这些发现加深了我们对BRCA 1/2变异和不同人群相关癌症风险的认识，表明对非欧洲人群潜在癌症相关变异的认识存在差距，并表明在不同患者人群中进行基因组筛查可能是识别风险个体的有效工具。
Background Pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant-positive individuals in the general population are unaware of their risk, and little is known about prevalence in non-European populations. We investigated BRCA1/2 prevalence and impact in the electronic health record (EHR)-linked BioMe Biobank in New York City. Methods Exome sequence data from 30,223 adult BioMe participants were evaluated for pathogenic variants in BRCA1/2. Prevalence estimates were made in population groups defined by genetic ancestry and self-report. EHR data were used to evaluate clinical characteristics of variant-positive individuals. Results There were 218 (0.7%) individuals harboring expected pathogenic variants, resulting in an overall prevalence of 1 in 139. The highest prevalence was in individuals with Ashkenazi Jewish (AJ; 1 in 49), Filipino and other Southeast Asian (1 in 81), and non-AJ European (1 in 103) ancestry. Among 218 variant-positive individuals, 112 (51.4%) harbored known founder variants: 80 had AJ founder variants (BRCA1 c.5266dupC and c.68_69delAG, and BRCA2 c.5946delT), 8 had a Puerto Rican founder variant (BRCA2 c.3922G>T), and 24 had one of 19 other founder variants. Non-European populations were more likely to harbor BRCA1/2 variants that were not classified in ClinVar or that had uncertain or conflicting evidence for pathogenicity (uncertain/conflicting). Within mixed ancestry populations, such as Hispanic/Latinos with genetic ancestry from Africa, Europe, and the Americas, there was a strong correlation between the proportion of African genetic ancestry and the likelihood of harboring an uncertain/conflicting variant. Approximately 28% of variant-positive individuals had a personal history, and 45% had a personal or family history of BRCA1/2-associated cancers. Approximately 27% of variant-positive individuals had prior clinical genetic testing for BRCA1/2. However, individuals with AJ founder variants were twice as likely to have had a clinical test (39%) than those with other pathogenic variants (20%). Conclusions These findings deepen our knowledge about BRCA1/2 variants and associated cancer risk in diverse populations, indicate a gap in knowledge about potential cancer-related variants in non-European populations, and suggest that genomic screening in diverse patient populations may be an effective tool to identify at-risk individuals.