September 22, 2019  |  

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

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

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.

Journal: Nature genetics
DOI: 10.1038/ng.3520
Year: 2016

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