Malignant pleural mesothelioma: Germline variants in DNA repair genes may steer tailored treatment. (March 2022)

• Record Type: Journal Article
• Authors: Sculco, Marika; La Vecchia, Marta; Aspesi, Anna; Pinton, Giulia; Clavenna, Michela G.; Casalone, Elisabetta; Allione, Alessandra; Grosso, Federica; Libener, Roberta; Muzio, Alberto; Rena, Ottavio; Baietto, Guido; Parini, Sara; Boldorini, Renzo; Giachino, Daniela; Papotti, Mauro; Scagliotti, Giorgio V.; Migliore, Enrica; Mirabelli, Dario; Moro, Laura; Magnani, Corrado; Ferrante, Daniela; Matullo, Giuseppe; Dianzani, Irma
• Is Part Of: European journal of cancer. Volume 163(2022)
• Page Start: 44
• Page End: 54
• Publication Date: 2022-03
• Subjects: Mesothelioma -- DNA repair genes -- Synthetic lethality -- Tazemetostat -- Germline variants; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2021.12.023
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Introduction: 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. Aim: 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. Methods: 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. Results: 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). Conclusions: Overall these data suggest that patients with MPM and DNA repair insufficiency may benefit from this treatment, which induces synthetic lethality. Highlights: Germline pathogenic variants (PVs) are found in 7% of unselected patients with malignant pleural mesothelioma (MPM). Carriers of these PVs are more sensitive to asbestos than non-mutated patients. Most of these PVs occur in DNA repair genes that may be druggable. Tazemetostat targets MPM spheroids defective for DNA repair master gene ataxia telangiectasia mutated ( ATM ).