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

被引：698

作者：

Bueno, Raphael ^{[1
,2
,3
]}

Stawiski, Eric W. ^{[4
,5
]}

Goldstein, Leonard D. ^{[4
,5
]}

Durinck, Steffen ^{[4
,5
]}

De Rienzo, Assunta ^{[1
,2
,3
]}

Modrusan, Zora ^{[5
]}

Gnad, Florian ^{[4
]}

Nguyen, Thong T. ^{[5
]}

Jaiswal, Bijay S. ^{[5
]}

Chirieac, Lucian R. ^{[3
,6
]}

Sciaranghella, Daniele ^{[1
,2
,3
]}

Dao, Nhien ^{[1
,2
,3
]}

Gustafson, Corinne E. ^{[1
,2
,3
]}

Munir, Kiara J. ^{[2
,3
]}

Hackney, Jason A. ^{[4
]}

Chaudhuri, Amitabha ^{[7
]}

Gupta, Ravi ^{[7
]}

Guillory, Joseph ^{[5
]}

Toy, Karen ^{[5
]}

Ha, Connie ^{[5
]}

Chen, Ying-Jiun ^{[5
]}

Stinson, Jeremy ^{[5
]}

Chaudhuri, Subhra ^{[5
]}

Zhang, Na ^{[5
]}

Wu, Thomas D. ^{[4
]}

Sugarbaker, David J. ^{[8
]}

de Sauvage, Frederic J. ^{[9
]}

Richards, William G. ^{[1
,2
,3
]}

Seshagiri, Somasekar ^{[5
]}

机构：

[1] Brigham & Womens Hosp, Lung Ctr, Div Thorac Surg, 75 Francis St, Boston, MA 02115 USA

[2] Brigham & Womens Hosp, Int Mesothelioma Program, 75 Francis St, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Boston, MA USA

[4] Genentech Inc, Bioinformat & Computat Biol Dept, San Francisco, CA 94080 USA

[5] Genentech Inc, Mol Biol Dept, San Francisco, CA 94080 USA

[6] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA

[7] MedGenome Labs Pvt Ltd, Bioinformat Dept, Bangalore, Karnataka, India

[8] Baylor Coll Med, Div Thorac Surg, Houston, TX 77030 USA

[9] Genentech Inc, Mol Oncol Dept, San Francisco, CA 94080 USA

来源：

NATURE GENETICS | 2016年 / 48卷 / 04期

关键词：

DIFFERENTIAL EXPRESSION ANALYSIS; SOMATIC MUTATIONS; BIOCONDUCTOR PACKAGE; CANCER; RNA; DISCOVERY; DIAGNOSIS; DELETION; REVEALS; BAP1;

D O I：

10.1038/ng.3520

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 (similar to 2%; 4/216) and TRAF7 (similar to 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.

引用

页码：407 / +

页数：13

共 100 条

[1] Deciphering Signatures of Mutational Processes Operative in Human Cancer [J].

Alexandrov, Ludmil B. ;

Nik-Zainal, Serena ;

Wedge, David C. ;

Campbell, Peter J. ;

Stratton, Michael R. .

CELL REPORTS, 2013, 3 (01) :246-259

[2] A mouse model recapitulating molecular features of human mesothelioma [J].

Altomare, DA ;

Vaslet, CA ;

Skele, KL ;

De Rienzo, A ;

Devarajan, K ;

Jhanwar, SC ;

McClatchey, AI ;

Kane, AB ;

Testa, JR .

CANCER RESEARCH, 2005, 65 (18) :8090-8095

[3] Differential expression analysis for sequence count data [J].

Anders, Simon ;

Huber, Wolfgang .

GENOME BIOLOGY, 2010, 11 (10)

[4] Detecting differential usage of exons from RNA-seq data [J].

Anders, Simon ;

Reyes, Alejandro ;

Huber, Wolfgang .

GENOME RESEARCH, 2012, 22 (10) :2008-2017

[5] The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans [J].

Ardlie, Kristin G. ;

DeLuca, David S. ;

Segre, Ayellet V. ;

Sullivan, Timothy J. ;

Young, Taylor R. ;

Gelfand, Ellen T. ;

Trowbridge, Casandra A. ;

Maller, Julian B. ;

Tukiainen, Taru ;

Lek, Monkol ;

Ward, Lucas D. ;

Kheradpour, Pouya ;

Iriarte, Benjamin ;

Meng, Yan ;

Palmer, Cameron D. ;

Esko, Tonu ;

Winckler, Wendy ;

Hirschhorn, Joel N. ;

Kellis, Manolis ;

MacArthur, Daniel G. ;

Getz, Gad ;

Shabalin, Andrey A. ;

Li, Gen ;

Zhou, Yi-Hui ;

Nobel, Andrew B. ;

Rusyn, Ivan ;

Wright, Fred A. ;

Lappalainen, Tuuli ;

Ferreira, Pedro G. ;

Ongen, Halit ;

Rivas, Manuel A. ;

Battle, Alexis ;

Mostafavi, Sara ;

Monlong, Jean ;

Sammeth, Michael ;

Mele, Marta ;

Reverter, Ferran ;

Goldmann, Jakob M. ;

Koller, Daphne ;

Guigo, Roderic ;

McCarthy, Mark I. ;

Dermitzakis, Emmanouil T. ;

Gamazon, Eric R. ;

Im, Hae Kyung ;

Konkashbaev, Anuar ;

Nicolae, Dan L. ;

Cox, Nancy J. ;

Flutre, Timothee ;

Wen, Xiaoquan ;

Stephens, Matthew .

SCIENCE, 2015, 348 (6235) :648-660

[6] Updated patterns of failure after multimodality therapy for malignant pleural mesothelioma [J].

Baldini, Elizabeth H. ;

Richards, William G. ;

Gill, Ritu R. ;

Goodman, Brian M. ;

Winfrey, Olivia K. ;

Eisen, Hannah M. ;

Mak, Raymond H. ;

Chen, Aileen B. ;

Kozono, David E. ;

Bueno, Raphael ;

Sugarbaker, David J. .

JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY, 2015, 149 (05) :1374-1381

[7] Reactive oxygen species a double-edged sword for mesothelioma [J].

Benedetti, Serena ;

Nuvoli, Barbara ;

Catalani, Simona ;

Galati, Rossella .

ONCOTARGET, 2015, 6 (19) :16848-16865

[8] HIGH-FREQUENCY OF INACTIVATING MUTATIONS IN THE NEUROFIBROMATOSIS TYPE-2 GENE (NF2) IN PRIMARY MALIGNANT MESOTHELIOMAS [J].

BIANCHI, AB ;

MITSUNAGA, SI ;

CHENG, JQ ;

KLEIN, WM ;

JHANWAR, SC ;

SEIZINGER, B ;

KLEY, N ;

KLEINSZANTO, AJP ;

TESTA, JR .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (24) :10854-10858

[9] HLA typing from RNA-Seq sequence reads [J].

Boegel, Sebastian ;

Loewer, Martin ;

Schaefer, Michael ;

Bukur, Thomas ;

de Graaf, Jos ;

Boisguerin, Valesca ;

Tuereci, Oezlem ;

Diken, Mustafa ;

Castle, John C. ;

Sahin, Ugur .

GENOME MEDICINE, 2012, 4

[10] The spliceosome as a target of novel antitumour drugs [J].

Bonnal, Sophie ;

Vigevani, Luisa ;

Valcarcel, Juan .

NATURE REVIEWS DRUG DISCOVERY, 2012, 11 (11) :847-859

← 1 2 3 4 5 6 7 8 9 10 →