Genetic Susceptibility in MAlignant Pleural Mesothelioma: Clinical Implication of GermliNE variaTionS

Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm of the pleural mesothelium, mainly associated to asbestos exposure, still lacking effective therapies. Asbestos is a not-mutagenic agent: its nanosized fibres directly interact with tyrosine kinases (TKs) (e.g. EGFR) and may induce inappropriate receptor dimerization and activation, in absence of activating somatic mutations. TK receptor activation initiates cell signaling cascades and carcinogenesis. Asbestos, thus, induces the generation of an inflammatory immunosuppressive microenvironment that may support tumor growth in individuals with genetic predisposition (2). Consequently, the lack of actionable tumor targets together with the heterogeneous stroma, support the failure of modern drugs, both TK and immune-checkpoint inhibitors (TKIs, ICIs). In this complex context, the role of germline changes in MPM remains largely unexplored, except for changes in the BAP1 gene which are known to predispose to the disease (3). The main goal of the study is to look for germline changes of a panel of genes involved in microenvironment infiltration modulation, drug response and cancer predisposition. The study will be performed in parallel on blood samples obtained from asbestos-exposed subjects and on MPM patients. This approach will allow: detection of putative germline signatures associated with MPM onset predisposition (or even protection) with prognostic and predictive implications. The genetic characterization of MPM has not been fully clarified until now due to the significant inter-patient variability and to the scarcely reported somatic aberrations. Most of genetic alterations in MPM are loss of function of tumor suppressor genes or caretaker genes. Thus, the present project aimed at deeply investigate the germline variation in MPM and exposed population to determine host factors involved in MPM promotion. Pathogenic germline variants in MPM are often involved in DNA damage repair and chromatin