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Nat Genet. 2016 Apr;48(4):407-16. doi: 10.1038/ng.3520. Epub 2016 Feb 29.

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

Author information

1
Division of Thoracic Surgery, The Lung Center and the International Mesothelioma Program, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
2
Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.
3
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
4
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
5
Bioinformatics Department, MedGenome Labs, Pvt., Ltd., Narayana Health City, Bangalore, India.
6
Division of Thoracic Surgery, Baylor College of Medicine, Houston, Texas, USA.
7
Molecular Oncology Department, Genentech, Inc., South San Francisco, California, USA.

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.

PMID:
26928227
DOI:
10.1038/ng.3520
[Indexed for MEDLINE]

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