Journal Article

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

Ha, Connie, Modrusan, Zora, Gustafson, Corinne E, Chen, Ying-Jiun, Seshagiri, Somasekar, Chirieac, Lucian R, Goldstein, Leonard D, Chaudhuri, Amitabha, Nguyen, Thong T, Munir, Kiara J, Hackney, Jason A, Toy, Karen, De Rienzo, Assunta, Richards, William G, Sciaranghella, Daniele, Chaudhuri, Subhra, Stawiski, Eric W, Guillory, Joseph, Dao, Nhien, Zhang, Na, de Sauvage, Frederic J, Stinson, Jeremy, Wu, Thomas D, Bueno, Raphael, Gnad, Florian, Durinck, Steffen, Jaiswal, Bijay S, Gupta, Ravi, Sugarbaker, David J

2016

Overview

Raphael Bueno, Eric Stawiski, Somasekar Seshagiri and colleagues present a comprehensive genomic analysis of malignant pleural mesothelioma. They identify four distinct molecular subtypes using RNA-seq data and highlight recurrent somatic mutations, gene fusions and splicing alterations. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45/23 / 45/91 / 631/208/212 / 631/67/1641 / Agriculture / Alternative Splicing / Animal Genetics and Genomics / Bioinformatics / Biomedicine / Cancer Research / Cell Line, Tumor / Cellular signal transduction / Classification / Confidence intervals / Development and progression / DNA Mutational Analysis / Exome / Gene expression / Gene Function / Gene mutations / Genetic aspects / Genomes / Genomics / Health aspects / Human Genetics / Humans / Identification and classification / Kaplan-Meier Estimate / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - mortality / Medical prognosis / Mesothelioma / Mesothelioma - genetics / Mesothelioma - metabolism / Mesothelioma - mortality / Mesothelioma, Malignant / Mutation / Oncogene Proteins, Fusion - genetics / Oncogene Proteins, Fusion - metabolism / Patients / Phosphoproteins - genetics / Phosphoproteins - metabolism / Pleural Neoplasms - genetics / Pleural Neoplasms - metabolism / Pleural Neoplasms - mortality / Polymorphism, Single Nucleotide / Principal components analysis / Proportional Hazards Models / Protein Isoforms - genetics / Protein Isoforms - metabolism / Ribonucleoprotein, U2 Small Nuclear - genetics / Ribonucleoprotein, U2 Small Nuclear - metabolism / RNA Splicing Factors / Studies / Womens health