Malignant pleural mesothelioma: Germline variants in DNA repair genes may steer tailored treatment.

Malignant pleural mesothelioma (MPM) is a tumour associated with asbestos exposure. Approximately, 10% of patients with MPM carry a germline pathogenic variant (PV), mostly in DNA repair genes, suggesting the occurrence of inherited predispositions. This article aimed to 1) search for new predisposing genes and assess the prevalence of PVs in DNA repair genes, by next-generation sequencing (NGS) analysis of germline DNA from 113 unselected patients with MPM and 2) evaluate whether these patients could be sensitive to tailored treatments. NGS was performed using a custom panel of 107 cancer-predisposing genes. To investigate the response to selected drugs in conditions of DNA repair insufficiency, we created a three-dimensional-MPM cell model that had a defect in ataxia telangiectasia mutated (ATM), the master regulator of DNA repair. We identified PVs in approximately 7% of patients with MPM (8/113) and a new PV in BAP1 in a further patient with familial MPM. Most of these PVs were in genes involved or supposedly involved in DNA repair (BRCA1, BRIP1, CHEK2, SLX4, FLCN and BAP1). In vitro studies showed apoptosis induction in ATM-silenced/inhibited MPM spheroids treated with an enhancer of zeste homologue 2 inhibitor (tazemetostat). Overall these data suggest that patients with MPM and DNA repair insufficiency may benefit from this treatment, which induces synthetic lethality.

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Déclaration de conflit d'intérêts

Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Grosso reports outside the submitted work personal fees for advisory role, speaker engagements and travel and accommodation expenses from Merck Sharp & Dohme (MSD), Novocure, Bristol Meyer Squibb, Boehringer Ingelheim, PharmaMar and Novartis. Scagliotti reports outside the submitted work personal fees for lectures, presentations, speaker bureaus, article writing and educational events from Eli Lilly, Roche, Pfizer, AstraZeneca, Novartis, MSD, Takeda and Beigene. Scagliotti reports participation on a data safety monitoring board and advisory board from Beigene, Takeda, MSD, Novartis, AstraZeneca, Pfizer, Roche and Eli Lilly outside the submitted work. Mirabelli received payment to discuss court cases with asbestos-related neoplasms from the public prosecution office at the Verbania Court and Turin Court. Magnani received payment for participation in different trials regarding asbestos-related diseases from the public prosecution office and research funding (BRIC Project) from INAIL outside the submitted work. Dianzani has been appointed by the public prosecution office to discuss court cases with asbestos-related neoplasms. The remaining authors declare no conflicts of interest.