Hereditary risk in malignant mesothelioma

Malignant mesothelioma (MM) is a rare and aggressive cancer caused by asbestos exposure. MM has a long latency period (>20 years) and the median survival is 9-18 months after diagnosis. Presently, no biomarkers are recommended for MM. A genetic predisposition was supposed since only 10-17% of individuals highly exposed to asbestos develop MM and some families present multiple MM cases. Germline variants in BAP1 are responsible for an inherited cancer syndrome that includes MM in its cancer constellation. Only 6-7% of familial MM carry BAP1 germline pathogenic variants (PVs), suggesting that other genes may predispose to MM. We and others demonstrated that ~10% of MM patients carried PVs in cancer-predisposing genes, mostly in homologous recombination repair (HRR) genes. My PhD studies aimed to: investigate the prevalence of germline PVs in BAP1 and other cancer-predisposing genes in MM patients, identify early non-invasive prognostic biomarkers by DNA methylation analysis. We found that the prevalence of BAP1 germline PVs in 56 patients with familial MM was 7.1%. We analysed 113 MM patients by targeted next-generation sequencing: 13 patients carried germline PVs in cancer-predisposing genes, especially in HRR genes. We assessed the quantification of asbestos exposure including patients of this study and those reported in previous work by our group and found a statistically significant lower asbestos exposure in PV carriers than in non-mutated patients (p=0.0005). These data suggest that patients with defects in DNA repair genes are less proficient at repairing the DNA damage induced by asbestos and show increased susceptibility to asbestos-induced MM. They may benefit from drugs that induce synthetic lethality. Finally, we investigated DNA methylation profile in 159 MM cases, identifying the hypomethylation of FKBP5. This gene has been found deregulated in several cancer tissues and associated with chemoresistance.