Brief Report: Novel Germline Mutations in DNA Damage Repair in Patients with Malignant Pleural Mesotheliomas.

Abstract

INTRODUCTION\nAlthough 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).\n\n\nMETHODS\nWe 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.\n\n\nRESULTS\nOf 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.\n\n\nCONCLUSIONS\nOur 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.