Abstract LB-331: Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations

Abstract

Abstract Malignant pleural mesothelioma (MPM) is an aggressive cancer arising from the mesothelial cells of the pleura. About 80% of mesothelioma cases are linked to asbestos exposure, while the remainder may be related to prior chest radiation, genetic predisposition or spontaneous occurrence. We analyzed transcriptomes (n = 211), whole exomes (n = 99), and targeted exomes (n = 103) from 216 malignant pleural mesothelioma (MPM) tumors. Four distinct molecular subtypes, sarcomatoid (S), epithelioid (E), biphasic-E, and biphasic-S were identified using RNA-seq data. Using exome analysis we found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1, and DDX51 to be significantly mutated MPM genes. We identified recurrent mutations in several genes including splice complex factor SF3B1 (∼2% [4/216]) and TRAF7 (∼2% [5/216]). SF3B1 mutant samples showed a distinct splicing profile compared to wild-type tumors. Mutations in TRAF7 occurred primarily in the WD40 domain and except in one case were mutually exclusive with NF2 mutations. We found recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2. We analyzed the tumors for infiltrating immune cells and found that M2 macrophage to T-cell ratio was predictive of reduced overall survival. Further we found sarcomatoid subtype had a significantly higher level of PD-L1 expression suggesting that this group might be prioritized for checkpoint inhibitor therapy. Integrated analysis of alterations identified changes in Hippo, mTOR, Histone methylation, RNA helicase and p53 signaling pathways in MPMs. Overall our study significantly expands on the previous genomic studies and provides a comprehensive genomics profile of mesothelioma and identifies several previously unknown alterations and biological pathways that are potential targets for drug discovery and treatment. Incorporating genomic analysis for detection of actionable alterations as part of MPM patient care will help in developing rational individualized therapy. Citation Format: Somasekar Seshagiri, Eric Stawiski, Leonard Goldstein, Steffen Durinck, Zora Modrusan, Florian Gnad, Thong T. Nguyen, Bijay Jaiswal, Assunta De Rienzo, William Richards, Raphael Bueno. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-331.