INTRODUCTION Although next-generation sequencing (NGS) has brought insight into critical mutations or pathways (e.g. DNA damage sensing and repair) involved in the etiology of many cancers and directed new screening, prevention, and therapeutic approaches for patients and families, NGS has only recently been utilized in malignant pleural mesotheliomas (MPMs). METHODS We analyzed blood samples from patients with MPM using the NGS platform MSK-IMPACT™ to explore cancer-predisposing genes. Loss of function variants or pathogenic entries were identified and clinicopathologic information was collected. RESULTS Of 84 patients with MPM, 12% (10/84) had pathogenic variants. Clinical characteristics were similar between cohorts, although patients with germline pathogenic variants were more likely to have more than 2 first-degree family members with cancer than those without germline mutations (40% vs 12%; Fisher's exact test, p < 0.05). Novel deleterious variants in mesotheliomas included MSH3 (1% [1/84]; 95% CI: 0-7%), BARD1 (1% [1/84]; 95% CI: 0-7%), and RECQL4 (2% [2/84]; 95% CI: 0-9%). Pathogenic variants previously reported on germline testing in patients with mesotheliomas were BAP1 (4% [3/84]; 95% CI: 1-10%), BRCA2 (1% [1/84]; 95% CI: 0-7%), and MRE11A (1% [1/84]; 95% CI: 0-7%). One patient (1% [1/84]; 95% CI: 0-7%) had a likely pathogenic alteration in SHQ1 that has not been associated with a heritable susceptibility to cancer. CONCLUSIONS Our study lends further support for the role of aberrations in DNA damage repair genes in the pathogenesis of malignant pleural mesotheliomas and suggests that targeting members of these pathways for screening and treatment warrants further studying.

中文翻译：

---

简报：恶性胸膜间皮瘤患者 DNA 损伤修复中的新种系突变

引言 尽管新一代测序 (NGS) 已经深入了解了许多癌症病因学中涉及的关键突变或途径（例如 DNA 损伤感知和修复），并为患者和家属提供了新的筛查、预防和治疗方法，但 NGS 仅最近被用于恶性胸膜间皮瘤（MPMs）。方法 我们使用 NGS 平台 MSK-IMPACT™ 分析了 MPM 患者的血液样本，以探索癌症易感基因。鉴定了功能变异或致病性条目的丧失并收集了临床病理学信息。结果 在 84 名 MPM 患者中，12% (10/84) 具有致病性变异。队列之间的临床特征相似，尽管具有种系致病性变异的患者比没有种系突变的患者更有可能有超过 2 个一级家族成员患有癌症（40% 对 12%；Fisher 精确检验，p < 0.05）。间皮瘤中的新型有害变异包括 MSH3（1% [1/84]；95% CI：0-7%）、BARD1（1% [1/84]；95% CI：0-7%）和 RECQL4（2 % [2/84]；95% CI：0-9%）。先前在间皮瘤患者的生殖系检测中报告的致病变异为 BAP1 (4% [3/84]；95% CI：1-10%)、BRCA2 (1% [1/84]；95% CI：0-7%) ) 和 MRE11A (1% [1/84]; 95% CI: 0-7%)。一名患者 (1% [1/84]; 95% CI: 0-7%) 在 SHQ1 中可能有致病性改变，但与遗传性癌症易感性无关。