Raphael Bueno1,8, Eric W Stawiski2,3,8, Leonard D Goldstein2,3,8, Steffen Durinck2,3,8, Assunta De Rienzo1,8, Zora Modrusan3,8, Florian Gnad2,8, Thong T Nguyen3,8, Bijay S Jaiswal3,8, Lucian R Chirieac4, Daniele Sciaranghella1, Nhien Dao1, Corinne E Gustafson1, Kiara J Munir1, Jason A Hackney2, Amitabha Chaudhuri5, Ravi Gupta5, Joseph Guillory3, Karen Toy3, Connie Ha3, Ying-Jiun Chen3, Jeremy Stinson3, Subhra Chaudhuri3, Na Zhang3, Thomas D Wu2, David J Sugarbaker6, Frederic J de Sauvage7, William G Richards1 & Somasekar Seshagiri3
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.