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Development of precision medicine for malignant pleural mesothelioma (MPM) requires a deep knowledge of tumor heterogeneity. Histologic and molecular classifications and histo‐molecular gradients have been proposed to describe heterogeneity, but a deeper understanding of gene mutations in the context of MPM heterogeneity is required and the associations between mutations and clinical data need to be refined. We characterized genetic alterations on one of the largest MPM series (266 tumor samples), well annotated with histologic, molecular and clinical data of patients. Targeted next‐generation sequencing was performed focusing on the major MPM mutated genes and the TERT promoter. Molecular heterogeneity was characterized using predictors allowing classification of each tumor into the previously described molecular subtypes and the determination of the proportion of epithelioid‐like and sarcomatoid‐like components (E/S.scores). The mutation frequencies are consistent with literature data, but this study emphasized that TERT promoter, not considered by previous large sequencing studies, was the third locus most affected by mutations in MPM. Mutations in TERT promoter, NF2, and LATS2 were more frequent in nonepithelioid MPM and positively associated with the S.score. BAP1, NF2, TERT promoter, TP53, and SETD2 mutations were enriched in some molecular subtypes. NF2 mutation rate was higher in asbestos unexposed patient. TERT promoter, NF2, and TP53 mutations were associated with a poorer overall survival. Our findings lead to a better characterization of MPM heterogeneity by identifying new significant associations between mutational status and histologic and molecular heterogeneity. Strikingly, we highlight the strong association between new mutations and overall survival., Our comprehensive genetic characterization of key‐altered genes including TERT promoter in malignant pleural mesothelioma led to the identification of new significant associations between the mutational status and the histological and molecular classifications. Our findings allow a better understanding of the genetic landscape in the context of tumor heterogeneity and highlight the high prognostic value of gene mutations in mesothelioma.

International audience; This study was undertaken to determine the healthcare burden of malignant pleural mesothelioma (MPM) in France and to analyze its associations with socioeconomic deprivation, population density, and management outcomes. A national hospital database was used to extract incident MPM patients in years 2011 and 2012. Cox models were used to analyze 1- and 2-year survival according to sex, age, co-morbidities, management, population-density index, and social deprivation index. The analysis included 1,890 patients (76% men; age: 73.6 ± 10.0 years; 84% with significant co-morbidities; 57% living in urban zones; 53% in highly underprivileged areas). Only 1% underwent curative surgical procedure; 65% received at least one chemotherapy cycle, 72% of them with at least one pemetrexed and/or bevacizumab administration. One- and 2-year survival rates were 64% and 48%, respectively. Median survival was 14.9 (95% CI: 13.7-15.7) months. The mean cost per patient was 27,624 ± 17,263 euros (31% representing pemetrexed and bevacizumab costs). Multivariate analyses retained men, age >70 years, chronic renal failure, chronic respiratory failure, and never receiving pemetrexed as factors of poor prognosis. After adjusting the analysis to age, sex, and co-morbidities, living in rural/semi-rural area was associated with better 2-year survival (HR: 0.83 [95% CI: 0.73-0.94]; P < 0.01); social deprivation index was not significantly associated with survival. With approximately 1,000 new cases per year in France, MPMs represents a significant national health care burden. Co-morbidities, sex, age, and living place appear to be significant factors of prognosis.