Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations

Abstract

We analyzed transcriptomes (n = 211), whole exomes (n = 99) and targeted exomes (n = 103) from 216 malignant pleural mesothelioma (MPM) tumors. Using RNA-seq data, we identified four distinct molecular subtypes: sarcomatoid, epithelioid, biphasic-epithelioid (biphasic-E) and biphasic-sarcomatoid (biphasic-S). Through exome analysis, we found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51 to be significantly mutated (q-score ≥ 0.8) in MPMs. We identified recurrent mutations in several genes, including SF3B1 (∼2%; 4/216) and TRAF7 (∼2%; 5/216). SF3B1-mutant samples showed a splicing profile distinct from that of wild-type tumors. TRAF7 alterations occurred primarily in the WD40 domain and were, except in one case, mutually exclusive with NF2 alterations. We found recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2. Through integrated analyses, we identified alterations in Hippo, mTOR, histone methylation, RNA helicase and p53 signaling pathways in MPMs.

Novel systemic therapy against malignant pleural mesothelioma

“…A comprehensive genomic analysis identified mutations in BAP1 in 23% of MPM samples (117). Similarly, somatic mutations in BAP1 have been reported in approximately 20% of cases of MPM (118) and linkage analysis demonstrated that germ-line mutations in BAP1 are associated with familial MPM (16).…”

“…Somatic mutations leading to loss of NF2 have been described in numerous cancers, including MPM. The recently published comprehensive genomic profiling of MPM identified mutations in NF-2 in 19% of cases (117).…”

Mesothelioma families without inheritance of a BAP1 predisposing mutation

“…Those of pathogenic significance have been described in association with BAP1-TPDS malignancies [4,21,[24][25][26][27][28]. On the other hand, somatic mutations of BAP1 are a frequent event in MM [26,28,29], with a variable rate of occurrence depending on the molecular assay used. Somatic mutations described to date are both nucleotide-level and chromosomal mutations [30].…”

Targeting the epigenome in malignant pleural mesothelioma

“…Collectively, these data support evaluation of DNA demethylating agents in combination with immune checkpoint inhibitors in MPM. Despite evidence that 5-AZA augmented responses to anti-CTLA therapy in preclinical models, a better translational strategy might be to combine DNA demethylating agents with pembrolizumab given recent observations that this PD-L1 inhibitor mediated a 17% objective response rate in MPM patients (134), and high levels of PD-L1 expression in MPM-particularly sarcomatoid subtypes (3). Observations that combined decitabine/GSK126 or 5-AZA/entinostat treatment markedly augment efficacy of adoptively transferred CTL or anti-PD-L1 via up-regulation of Th1 signaling and inhibition of immunosuppressive myeloid derived suppressor cells within the tumor microenvironment in murine cancer models (113,135) support evaluation of such combinatorial regimens in clinical settings.…”

“…Recent advances in "omics" technologies have enabled comprehensive gene and transcriptome analyses that have provided considerable insight regarding the pathogenesis, prognosis, and treatment of MPM (2,3). Presently, less information is available regarding mechanisms and clinical relevance of epigenetic derangements in MPM (4,5).…”