Structural Variants at the BRCA1/2 Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma.
Structural Variants at the BRCA1/2 Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma.
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DOI：
10.1158/1078-0432.ccr-20-4068
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发表时间：
2021-06-01
期刊：
影响因子：
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通讯作者：
Semple CA
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文献类型：
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作者：
Ewing A;Meynert A;Churchman M;Grimes GR;Hollis RL;Herrington CS;Rye T;Bartos C;Croy I;Ferguson M;Lennie M;McGoldrick T;McPhail N;Siddiqui N;Dowson S;Glasspool R;Mackean M;Nussey F;McDade B;Ennis D;McMahon L;Matakidou A;Dougherty B;March R;Barrett JC;McNeish IA;Scottish Genomes Partnership;Biankin AV;Roxburgh P;Gourley C;Semple CA
肿瘤中BRCA1/2结构变异的丰度及其影响尚未得到充分了解。特别是，这些事件对同源重组修复缺陷（HRD）的影响尚未得到证实。
利用大量高级别浆液性卵巢癌的全基因组测序数据（N = 205）以及大多数肿瘤匹配的RNA - seq数据（N = 150），我们全面描述了BRCA1/2的突变和表达情况。
除了已知的短体细胞突变（SSMs）谱外，我们发现数百万碱基的结构变异（SVs）是这些肿瘤中BRCA1/2破坏的一个常见但未被充分认识的来源，并且我们发现整个队列中BRCA1/2基因座存在全基因组范围的大片段缺失富集。这些SVs除了影响那些受SSMs影响的患者（24%）外，还独立影响相当比例的患者（16%），导致同源重组修复缺陷（HRD）并影响患者生存。我们还详细描述了涉及两个基因座的SSMs和SVs的复合缺陷，表明在没有SSMs的情况下，BRCA1和BRCA2同时存在SVs时出现HRD的风险最高。此外，这些SVs在其他癌症类型中也大量存在且具有破坏性。
这些结果拓展了我们对HRD潜在突变情况的理解，增加了预计可从利用HRD的疗法中获益的患者数量，并表明目前在利用SV检测进行患者分层方面存在尚未开发的潜力。
The abundance and effects of structural variation at BRCA1/2 in tumours are not well understood. In particular, the impact of these events on homologous recombination repair deficiency (HRD) has yet to be demonstrated. Exploiting a large collection of whole genome sequencing data from high grade serous ovarian carcinoma (N=205) together with matched RNA-seq for the majority of tumours (N=150), we have comprehensively characterised mutation and expression at BRCA1/2. In addition to the known spectrum of short somatic mutations (SSMs), we discover that multi-megabase structural variants (SVs) are a frequent, unappreciated source of BRCA1/2 disruption in these tumours, and we find a genome wide enrichment for large deletions at the BRCA1/2 loci across the cohort. These SVs independently affect a substantial proportion of patients (16%) in addition to those affected by SSMs (24%), conferring homologous recombination repair deficiency (HRD) and impacting patient survival. We also detail compound deficiencies involving SSMs and SVs at both loci, demonstrating that the strongest risk of HRD emerges from combined SVs at both BRCA1 and BRCA2 in the absence of SSMs. Further, these SVs are abundant and disruptive in other cancer types. These results extend our understanding of the mutational landscape underlying HRD, increase the number of patients predicted to benefit from therapies exploiting HRD, and suggest there is currently untapped potential in SV detection for patient stratification.