Integrative Molecular Characterization of Malignant Pleural Mesothelioma
Authors: Hmeljak Julija , Sanchez-Vega Francisco , Hoadley Katherine A. , Shih Juliann , Stewart Chip , Heiman David , Tarpey Patrick , Danilova Ludmila , Drill Esther , Gibb Ewan A. , Bowlby Reanne , Kanchi Rupa , Osmanbeyoglu Hatice U. , Sekido Yoshitaka , Takeshita Jumpei , Newton Yulia , Graim Kiley , Gupta Manaswi , Gay Carl M. , Diao Lixia , Gibbs David L. , Thorsson Vesteinn , Iype Lisa , Kantheti Havish , Severson David T. , Ravegnini Gloria , Desmeules Patrice , Jungbluth Achim A. , Travis William D. , Dacic Sanja , Chirieac Lucian R. , Galateau-Sallé Françoise , Fujimoto Junya , Husain Aliya N. , Silveira Henrique C. , Rusch Valerie W. , Rintoul Robert C. , Pass Harvey , Kindler Hedy , Zauderer Marjorie G. , Kwiatkowski David J. , Bueno Raphael , Tsao Anne S. , Creaney Jenette , Lichtenberg Tara , Leraas Kristen , Bowen Jay ,   TCGA Research Network, Felau Ina , Zenklusen Jean Claude , Akbani Rehan , Cherniack Andrew D. , Byers Lauren A. , Noble Michael S. , Fletcher Jonathan A. , Robertson A. Gordon , Shen Ronglai , Aburatani Hiroyuki , Robinson Bruce W. , Campbell Peter , Ladanyi Marc , Aburatani Hiroyuki , Akbani Rehan , Ally Adrian , Anur Pavana , Armenia Joshua , Auman J. Todd , Balasundaram Miruna , Balu Saianand , Baylin Stephen B. , Becich Michael , Behrens Carmen , Beroukhim Rameen , Bielski Craig , Bodenheimer Tom , Bootwalla Moiz S. , Bowen Jay , Bowlby Reanne , Brooks Denise , Bueno Raphael , Byers Lauren Averett , Cárcano Flávio M. , Carlsen Rebecca , Carvalho Andre L. , Cherniack Andrew D. , Cheung Dorothy , Chirieac Lucian , Cho Juok , Chuah Eric , Chudamani Sudha , Cibulskis Carrie , Cope Leslie , Crain Daniel , Creaney Jenette , Curley Erin , Dacic Sanja , Danilova Ludmila , Rienzo Assunta De , DeFreitas Timothy , Demchok John A. , Dhalla Noreen , Dhir Rajiv , Diao Lixia , Drill Esther , Felau Ina , Feldman Michael , Ferguson Martin L. , Fletcher Jonathan A. , Fujimoto Junya , Fujimoto Junya , Fukuda Shiro , Gabriel Stacey B. , Sallé Françoise Galateau , Gao Jianjiong , Gardner Johanna , Gastier-Foster Julie M. , Gay Carl M. , Gehlenborg Nils , Gerken Mark , Getz Gad , Gibb Ewan A. , Gibbs David L. , Goparaju Chandra , Graim Kiley , Gross Benjamin , Guo Guangwu , Gupta Manaswi , Hasegawa Seiki , Haussler David , Hayes D. Neil , Heiman David I. , Heins Zachary , Hmeljak Julija , Hoadley Katherine A. , Holt Robert A. , Hoyle Alan P. , Husain Aliya , Hutter Carolyn M. , Iype Lisa , Jefferys Stuart R. , Jones Steven J.M. , Jones Corbin D. , Kanchi Rupa S. , Kasaian Katayoon , Kim Jaegil , Kindler Hedy , Kondo Nobuyuki , Krausz Thomas , Kundra Ritika , Kuribayashi Kozo , Kwiatkowski David J. , Ladanyi Marc , Lai Phillip H. , Laird Peter W. , Lawrence Michael S. , Lee Darlene , Leraas Kristen M. , Lichtenberg Tara M. , Lin Pei , Liu Jia , Liu Wenbin , Liu Eric Minwei , Lolla Laxmi , Longatto-Filho Adhemar , Lu Yiling , Luketich James , Ma Yussanne , Maglinte Dennis T. , Mallory David , Marra Marco A. , Mayo Michael , Meier Sam , Melamed Jonathan , Meng Shaowu , Meyerson Matthew , Mieczkowski Piotr A. , Mills Gordon B. , Moore Richard A. , Moran Cesar , Morris Scott , Mose Lisle E. , Mungall Andrew J. , Mungall Karen , Nakano Takashi , Naresh Rashi , Newton Yulia , Noble Michael S. , Ochoa Angelica , Osmanbeyoglu Hatice , Parker Joel S. , Pass Harvey I. , Paulauskis Joseph , Pennathur Arjun , Pennell Nathan A. , Penny Robert , Perou Charles M. , Pihl Todd , Ramirez Nilsa C. , Rassl Doris M. , Ravegnini Gloria , Reid Glen , Reis Rui M. , Reynolds Sheila M. , Rice David , Richards William G , Rintoul Robert C. , Roach Jeffrey , Robertson A. Gordon , Rusch Valerie , Sadeghi Sara , Saksena Gordon , Sanchez-Vega Francisco , Sander Chris , Sato Ayuko , Scapulatempo-Neto Cristovam , Schein Jacqueline E. , Schultz Nikolaus , Schumacher Steven E. , Seiwert Tanguy , Sekido Yoshitaka , Severson David T , Shelton Candace , Shelton Troy , Shen Ronglai , Sheridan Robert , Shi Yan , Shih Juliann , Shiraishi Yuichi , Shmulevich Ilya , Silveira Henrique C. S. , Simons Janae V. , Sipahimalani Payal , Skelly Tara , Sofia Heidi J. , Soloway Matthew G. , Spellman Paul , Stewart Chip , Stuart Josh , Sun Qiang , Takeshita Jumpei , Tam Angela , Tan Donghui , Tarnuzzer Roy , Tatsuno Kenji , Taylor Barry S , Thiessen Nina , Thompson Eric , Thorsson Vesteinn , Travis William D. , Tsao Anne , Tse Kane , Tsujimura Tohru , Valdivieso Federico , Van Den Berg David J. , van Zandwijk Nico , Veluvolu Umadevi , Viana Luciano S. , Voet Douglas , Wan Yunhu , Wang Zhining , Wang Jing , Weaver Joellen , Weinstein John N. , Weisenberger Daniel J. , Wilkerson Matthew D. , Wise Lisa , Wistuba Ignacio , Wong Tina , Wu Ye , Yamamoto Shogo , Yang Liming , Zauderer Marjorie G. , Zenklusen Jean C. , Zhang Jiashan , Zhang Hailei , Zhang Hongxin , Zmuda Erik 
Published: October 2018

Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options.

Significance:

Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM.

See related commentary by Aggarwal and Albelda, p. 1508.

This article is highlighted in the In This Issue feature, p. 1494