Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
J Thorac Oncol. 2020 Apr;15(4):655-660. doi: 10.1016/j.jtho.2019.12.111. Epub 2019 Dec 28.
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 has directed new screening, prevention, and therapeutic approaches for patients and families, it has only recently been used in malignant pleural mesotheliomas (MPMs).
We analyzed the blood samples from patients with MPM using the NGS platform MSK-IMPACT to explore cancer-predisposing genes. The loss-of-function variants or pathogenic entries were identified, and clinicopathologic information was collected.
Of 84 patients with MPM, 12% (10 of 84) had pathogenic variants. Clinical characteristics were similar between cohorts, although patients with germline pathogenic variants were more likely to have more than two first-degree family members with cancer than those without germline mutations (40% versus 12%; Fisher's exact test, p < 0.05). Novel, deleterious variants in mesotheliomas included MutS homolog 3 (1% [one of 84]; 95% confidence interval [CI]: 0%-7%), breast cancer gene 1-associated ring domain 1 (1% [one of 84]; 95% CI: 0%-7%), and RecQ-like helicase 4 (2% [two of 84]; 95% CI: 0%-9%). Pathogenic variants previously reported on germline testing in patients with mesotheliomas were breast cancer gene 1-associated protein 1 (4% [three of 84]; 95% CI: 1%-10%), breast cancer gene 2 (1% [one of 84]; 95% CI: 0%-7%), and MRE11 homolog, double strand break repair nuclease (1% [one of 84]; 95% CI: 0%-7%). One patient (1% [one of 84]; 95% CI: 0%-7%) had a likely pathogenic alteration in SHQ1, H/ACA ribonucleoprotein assembly factor that has not been associated with a heritable susceptibility to cancer.
Our study lends further support for the role of aberrations in DNA damage repair genes in the pathogenesis of MPMs and suggests that targeting the members of these pathways for screening and treatment warrants further study.
尽管下一代测序（NGS）已经深入了解了许多癌症发病机制中涉及的关键突变或途径（例如，DNA 损伤感应和修复），并为患者和家庭指导了新的筛查、预防和治疗方法，但它直到最近才被应用于恶性胸膜间皮瘤（MPM）。
我们使用 NGS 平台 MSK-IMPACT 分析了 MPM 患者的血液样本，以探索致癌易感基因。鉴定了功能丧失性变异或致病性条目，并收集了临床病理信息。
在 84 名 MPM 患者中，有 12%（10/84）存在致病性变异。两组患者的临床特征相似，尽管携带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两个以上一级亲属患有癌症（40%比 12%；Fisher 精确检验，p<0.05）。间皮瘤中发现的新的、有害的变异包括 MutS 同源物 3（1%[84 例中的 1 例]；95%置信区间[CI]：0%-7%）、乳腺癌基因 1 相关环域 1（1%[84 例中的 1 例]；95%CI：0%-7%）和 RecQ 样解旋酶 4（2%[84 例中的 2 例]；95%CI：0%-9%）。以前在 MPM 患者的种系检测中报告的致病性变异包括乳腺癌基因 1 相关蛋白 1（4%[84 例中的 3 例]；95%CI：1%-10%）、乳腺癌基因 2（1%[84 例中的 1 例]；95%CI：0%-7%）和 MRE11 同源物，双链断裂修复核酶（1%[84 例中的 1 例]；95%CI：0%-7%）。1 名患者（1%[84 例中的 1 例]；95%CI：0%-7%）存在 SHQ1 中可能的致病性改变，SHQ1 是一种尚未与遗传性癌症易感性相关的 H/ACA 核糖核蛋白组装因子。
我们的研究进一步支持 DNA 损伤修复基因异常在 MPM 发病机制中的作用，并表明针对这些途径的成员进行筛查和治疗值得进一步研究。
