PDF(Pubmed)
Abstract：
Prostate cancer (PCa) is highly heritable, with men of African ancestry at greatest risk and associated lethality. Lack of representation in genomic data means germline testing guidelines exclude for African men. Established that structural variations (SVs) are major contributors to human disease and prostate tumourigenesis, their role is under-appreciated in familial and therapeutic testing. Utilising a clinico-methodologically matched African (n = 113) versus European (n = 57) deep-sequenced PCa resource, we interrogated 42,966 high-quality germline SVs using a best-fit pathogenicity prediction workflow. We identified 15 potentially pathogenic SVs representing 12.4% African and 7.0% European patients, of which 72% and 86% met germline testing standard-of-care recommendations, respectively. Notable African-specific loss-of-function gene candidates include DNA damage repair MLH1 and BARD1 and tumour suppressors FOXP1, WASF1 and RB1. Representing only a fraction of the vast African diaspora, this study raises considerations with respect to the contribution of kilo-to-mega-base rare variants to PCa pathogenicity and African associated disparity.
摘要：
前列腺癌（PCa）是高度遗传性的，非洲血统的男性面临最大的风险和相关的致命性。基因组数据中缺乏代表性意味着种系测试指南排除了非洲男性。确定结构变异（SVs）是人类疾病和前列腺肿瘤发生的主要贡献者，他们的作用在家庭和治疗性测试中被低估。利用临床方法匹配的非洲（n=113）和欧洲（n=57）深度测序的PCa资源，我们使用最适合的致病性预测工作流程查询了42,966个高质量的种系SV.我们确定了15个潜在的致病性SVs，分别代表12.4%的非洲和7.0%的欧洲患者。其中72%和86%符合种系检测标准的护理建议，分别。值得注意的非洲特异性功能丧失基因候选包括DNA损伤修复MLH1和BARD1以及肿瘤抑制因子FOXP1、WASF1和RB1。仅代表广大非洲侨民的一小部分，这项研究提出了关于千碱基至巨型碱基罕见变异体对PCa致病性和非洲相关差异的贡献的考虑。
