Abstract
Simple SummaryMalignant pleura Mesothelioma (MPM) is an aggressive cancer arising from the mesothelial cells of the pleura. About 80% of mesothelioma cases are linked to asbestos exposure; the remainder may be related to prior chest radiation, genetic predisposition or spontaneous occurrence. Understanding the genetic alterations that drive MPM is critical for successful development of diagnostics, prognostics and personalized therapeutic modalities. Because MPM is rare, genomic studies are limited and have typically involved a small number of samples. The aim of our study was to understand the mutational landscape of MPM. Our analysis identified significantly mutated genes. This study on a rare tumor type will be important for patients “in real life”.Purpose: Malignant pleural mesothelioma (MPM) is an aggressive cancer. Data are not available in prospective trials on correlations between genetic alterations and outcomes of therapies. In this study, we assessed the genetic profile of MPM patients (pts) in tissue samples. Patients and Methods: From December 2016 to July 2018 (end of enrolment), 164 pts were enrolled. We evaluated by targeted sequencing the mutational profile of a panel of 34 genes: ACTB, ACTG1, ACTG2, ACTR1A, BAP1, CDH8, CDK4, CDKN2A, CDKN2B, COL3A1, COL5A2, CUL1, DHFR, GOT1, KDR, KIT, MXRA5, NF2, NFRKB, NKX6-2, NOD2, PCBD2, PDZK1IP1, PIK3CA, PIK3CB, PSMD13, RAPGEF6, RDX, SETDB1, TAOK1, TP53, TXNRD1, UQCRC1, XRCC6. Genetic profiling was correlated with clinical and pathological variables. Results: Overall, 110 pts (67%) from both treatment arms had samples available for molecular analysis. Median age was 63 years (45–81), 25.5% (n = 28) were females, and 74.5% (n = 82) were males. Tumor histotype was 81.8% (n = 90) epithelioid and 18.2% (n = 20) non-epithelioid; 28.5% of the tumors (n = 42) were stage IV, 71.5% (n = 68) were stage III. Targeted sequencing of tissue specimens identified 275 functional somatic mutations in the 34 genes analyzed. The number of mutated genes was positively associated with higher stage and metastatic disease (p = 0.025). RDX (42%), MXRA5 (23%), BAP1 (14%), and NF2 (11%) were the most frequently mutated genes. Mutations in RAPGEF6 (p = 0.03) and ACTG1 (p = 0.02) were associated with the non-epithelioid subtype, and mutations in BAP1 (p = 0.04) were related to progression-free survival (PFS) > 6 months. Conclusions: In the Ramucirumab Mesothelioma clinical trial (RAMES), mutation of the gene BAP1 is related to a prolonged PFS for patients treated with platinum/pemetrexed regimens (p = 0.04).
Highlights
Malignant pleural mesothelioma (MPM) is a rare, highly aggressive malignancy of the mesothelium that is usually diagnosed at an advanced stage
We found a significant correlation between number of mutations and PFS1 in our cohort
The results of previous whole-exome sequencing (WES) studies in MPM demonstrated that MPMs are characterized by a low mutational burden and a low genetic complexity, with very few significantly recurrent mutations
Summary
Malignant pleural mesothelioma (MPM) is a rare, highly aggressive malignancy of the mesothelium that is usually diagnosed at an advanced stage. Chemotherapy, which is the only available therapeutic option in the clinical setting, is modestly effective in MPM [1]. The proposed prognostic factors include clinical variables, radiological parameters at presentation, and pathological/molecular findings; the vast majority of these factors are not fully validated [2] Histologic type remains one of the most reliable prognostic factors, as the epithelioid subtype is associated with a better prognosis, and the sarcomatoid subtype with the worst one. A very rare condition is susceptibility to MPM in some families [6]. The subsequent discovery of an MPM risk in family members who are heterozygous for inherited/germline BAP1 mutations underscores the role of genetic alterations in this disease [7]
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