Genetic alterations of malignant pleural mesothelioma: association to tumor heterogeneity and overall survival.

Molecular Oncology 2020 February 21 [Link]

Quetel L, Meiller C, Assié JB, Blum Y, Imbeaud S, Montagne F, Tranchant R, de Wolf J, Caruso S, Copin MC, Hofman V, Gibault L, Badoual C, Pintilie E, Hofman P, Monnet I, Scherpereel A, Le Pimpec-Barthes F1, Zucman-Rossi J, Jaurand MC, Jean D


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 epithelioïd-like and sarcomatoïd-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 non-epithelioid MPM and positively associated to 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.