KRAS Mutations Are Associated with Shortened Survival in Patients with Epithelioid Malignant Pleural Mesothelioma

SIMPLE SUMMARY: Malignant pleural mesothelioma (MPM) is an aggressive tumor with implacable prognosis. It commonly harbors loss-of-function mutations in BAP1, NF2, CDKN2A and TP53, although their pathogenetic role is still uncertain since these genetic alterations, if isolated, do not cause MPM in mice models. The aim of our study was to describe the mutational landscape in a cohort of 29 patients with MPM and, eventually, correlate mutation profile with MPM phenotypic traits and prognosis. We report herein a correlation between the presence of KRAS mutations and prognosis of the epithelioid MPM and, moreover, the number of mutations correlated with shortened survival. Conversely, improved overall survival was associated with the presence of SNP p.V297I of the KDR gene. With the limitation of a relatively small series, these results contribute to the characterization of the mutation profile of MPM and its impact on prognosis. ABSTRACT: Malignant pleural mesothelioma (MPM) is an aggressive malignancy of the pleural surface that includes three major histologic subtypes, epitheliod, sarcomatoid and biphasic. Epithelioid mesothelioma is usually associated with better prognosis. The genetic mechanisms driving MPM, the possible target mutations and the correlation with overall survival remain largely unsettled. We performed target exome sequencing in 29 cases of MPM aimed at identifying somatic mutations and, eventually, their correlation with phenotypic traits and prognostic significance. We found that KRAS mutations, occurring in 13.7% of cases, were associated with shortened median survival (7.6 versus 32.6 months in KRAS wild-type; p = 0.005), as it was the occurrence of any ≥3 mutations (7.6 versus 37.6 months; p = 0.049). Conversely, the presence of KDR single nucleotide polymorphism p.V297I (rs2305948) resulted in a favorable variable for survival (NR versus 23.4 months; p = 0.026). With the intrinsic limitations of a small number of cases and patient heterogeneity, results of this study contribute to the characterization of the mutation profile of MPM and the impact of selected somatic mutations, and possibly KDR polymorphism, on prognosis.