Integrative Molecular Characterization of Malignant Pleural Mesothelioma
Julija Hmeljak(Memorial Sloan Kettering Cancer Center), Francisco Sánchez-Vega(Memorial Sloan Kettering Cancer Center), Katherine A. Hoadley(University of North Carolina at Chapel Hill), Juliann Shih(Broad Institute), Chip Stewart(University of North Carolina at Chapel Hill), David I. Heiman(University of North Carolina at Chapel Hill), Patrick Tarpey(Wellcome Sanger Institute), Ludmila Danilova(Sidney Kimmel Comprehensive Cancer Center), Esther Drill(Memorial Sloan Kettering Cancer Center), Ewan A. Gibb(Genome British Columbia), Reanne Bowlby(Canada's Michael Smith Genome Sciences Centre), Rupa S. Kanchi(The University of Texas MD Anderson Cancer Center), Hatice U. Osmanbeyoglu(Memorial Sloan Kettering Cancer Center), Yoshitaka Sekido(Aichi Cancer Center), Jumpei Takeshita(Tokyo University of Science), Yulia Newton(University of California, Santa Cruz), Kiley Graim(University of California, Santa Cruz), Manaswi Gupta(Broad Institute), Carl M. Gay(The University of Texas MD Anderson Cancer Center), Lixia Diao(The University of Texas MD Anderson Cancer Center), David L. Gibbs(Institute for Systems Biology), Vésteinn Thórsson(Institute for Systems Biology), Lisa Iype(Institute for Systems Biology), Havish S. Kantheti(The University of Texas at Dallas), David T. Severson(Brigham and Women's Hospital), Gloria Ravegnini(University of Bologna), Patrice Desmeules(Lung Institute), Achim A. Jungbluth(Memorial Sloan Kettering Cancer Center), William D. Travis(Memorial Sloan Kettering Cancer Center), Sanja Đačić(University of Pittsburgh Medical Center), Lucian R. Chirieac(Brigham and Women's Hospital), Françoise Galateau-Sallé(Centre Léon Bérard), Junya Fujimoto(The University of Texas MD Anderson Cancer Center), Aliya N. Husain(University of Illinois Chicago), Henrique C.S. Silveira(Hospital de Câncer de Barretos), Valerie W. Rusch(Memorial Sloan Kettering Cancer Center), Robert C. Rintoul(University of Cambridge), Harvey I. Pass(NYU Langone Health), Hedy L. Kindler(University of Chicago Medical Center), Marjorie G. Zauderer(Memorial Sloan Kettering Cancer Center), David J. Kwiatkowski(Brigham and Women's Hospital), Raphael Bueno(Brigham and Women's Hospital), Anne S. Tsao(The University of Texas MD Anderson Cancer Center), Jenette Creaney(The University of Western Australia), Tara M. Lichtenberg(Nationwide Children's Hospital), Kristen Leraas(Nationwide Children's Hospital), Jay Bowen(Nationwide Children's Hospital), Ina Felau(National Cancer Institute), Jean C. Zenklusen(National Cancer Institute), Rehan Akbani(The University of Texas MD Anderson Cancer Center), Andrew D. Cherniack(Broad Institute), Lauren A. Byers(Brigham and Women's Hospital), Michael S. Noble(Broad Institute), Jonathan A. Fletcher(University of Pittsburgh Medical Center), A. Gordon Robertson(Canada's Michael Smith Genome Sciences Centre), Ronglai Shen(Memorial Sloan Kettering Cancer Center), Hiroyuki Aburatani(Tokyo University of Science), B. W. Robinson(The University of Western Australia), Peter J. Campbell(Wellcome Sanger Institute), Marc Ladanyi(Memorial Sloan Kettering Cancer Center), Hiroyuki Aburatani(Tokyo University of Science), Rehan Akbani(The University of Texas MD Anderson Cancer Center), Adrian Ally, Pavana Anur, Joshua Armenia, J. Todd Auman, Miruna Balasundaram, Saianand Balu, Stephen B. Baylin, Michael J. Becich, Carmen Behrens, Rameen Beroukhim, Craig M. Bielski, Tom Bodenheimer, Moiz S. Bootwalla, Jay Bowen(Nationwide Children's Hospital), Reanne Bowlby(Canada's Michael Smith Genome Sciences Centre), Denise Brooks, Raphael Bueno(Brigham and Women's Hospital), Lauren Averett Byers(Brigham and Women's Hospital), Flavio Mavignier Cárcano, Rebecca Carlsen, André Lopes Carvalho, Andrew D. Cherniack(Broad Institute), Dorothy Cheung, Lucian R. Chirieac(Brigham and Women's Hospital), Juok Cho, Eric Chuah, Sudha Chudamani, Carrie Cibulskis, Leslie Cope, Daniel Crain, Jenette Creaney(The University of Western Australia), Erin Curley, Sanja Đačić(University of Pittsburgh Medical Center), Ludmila Danilova(Sidney Kimmel Comprehensive Cancer Center), Assunta De Rienzo, Timothy Defreitas, John A. Demchok, Noreen Dhalla, Rajiv Dhir, Lixia Diao(The University of Texas MD Anderson Cancer Center), Esther Drill(Memorial Sloan Kettering Cancer Center), Ina Felau(National Cancer Institute), Michaël Feldman, Martin L. Ferguson, Jonathan A. Fletcher(University of Pittsburgh Medical Center), Junya Fujimoto(The University of Texas MD Anderson Cancer Center), Junya Fujimoto(The University of Texas MD Anderson Cancer Center), Shiro Fukuda, Stacey Gabriel, Françoise Galateau-Sallé, Jianjiong Gao, Johanna Gardner, Julie M. Gastier-Foster, Carl M. Gay(The University of Texas MD Anderson Cancer Center), Nils Gehlenborg, Mark Gerken, Gad Getz, Ewan A. Gibb(Genome British Columbia), David L. Gibbs(Institute for Systems Biology), Chandra Goparaju, Kiley Graim(University of California, Santa Cruz), Benjamin Groß, Guangwu Guo, Manaswi Gupta(Broad Institute), Seiki Hasegawa, David Haussler, D. Neil Hayes, David I. Heiman(University of North Carolina at Chapel Hill), Zachary Heins, Julija Hmeljak(Memorial Sloan Kettering Cancer Center), Katherine A. Hoadley(University of North Carolina at Chapel Hill), Robert A. Holt, Alan P. Hoyle, Aliya N. Husain(University of Illinois Chicago), Carolyn M. Hutter, Lisa Iype(Institute for Systems Biology), Stuart R. Jefferys, Steven J.M. Jones, Corbin D. Jones, Rupa S. Kanchi(The University of Texas MD Anderson Cancer Center), Katayoon Kasaian, Jaegil Kim, Hedy L. Kindler(University of Chicago Medical Center), Nobuyuki Kondo, Thomas Krausz, Ritika Kundra, Kozo Kuribayashi, David J. Kwiatkowski(Brigham and Women's Hospital), Marc Ladanyi(Memorial Sloan Kettering Cancer Center), Phillip H. Lai, Peter W. Laird, Michael S. Lawrence, Darlene Lee, Kristen Leraas(Nationwide Children's Hospital), Tara M. Lichtenberg(Nationwide Children's Hospital), Pei Lin, Jia Liu, Wenbin Liu, Eric Minwei Liu, Laxmi Lolla, Adhemar Longatto‐Filho, Yiling Lu, James D. Luketich, Yussanne Ma, Dennis T. Maglinte, David Mallory, Marco A. Marra, Michael Mayo, Sam Meier, Jonathan Melamed, Shaowu Meng, Matthew Meyerson, Piotr A. Mieczkowski, Gordon B. Mills, Richard A. Moore, César A. Moran, Scott Morris, Lisle E. Mose, Andrew J. Mungall, Karen Mungall, Takashi Nakano, Rashi Naresh, Yulia Newton(University of California, Santa Cruz), Michael S. Noble(Broad Institute), Angelica Ochoa, Hatice U. Osmanbeyoglu(Memorial Sloan Kettering Cancer Center), Joel S. Parker, Harvey I. Pass(NYU Langone Health), Joseph Paulauskis, Arjun Pennathur, Nathan A. Pennell, Robert Penny, Charles M. Perou, Todd Pihl, Nilsa C. Ramirez, Doris M. Rassl, Gloria Ravegnini(University of Bologna), Glen Reid, Rui Manuel Reis, Sheila M. Reynolds, David C. Rice, William G. Richards, Robert C. Rintoul(University of Cambridge), Jeffrey Roach, A. Gordon Robertson(BC Cancer Agency), Valerie W. Rusch(Memorial Sloan Kettering Cancer Center), Sara Sadeghi, Gordon Saksena, Francisco Sánchez-Vega(Memorial Sloan Kettering Cancer Center), Chris Sander, Ayuko Sato, Cristovam Scapulatempo‐Neto, Jacqueline E. Schein, Nikolaus Schultz, Steven E. Schumacher, Tanguy Y. Seiwert, Yoshitaka Sekido(Aichi Cancer Center), David T. Severson(Brigham and Women's Hospital), Candace Shelton, Troy Shelton, Ronglai Shen(Memorial Sloan Kettering Cancer Center), Robert L. Sheridan, Yan Shi, Juliann Shih(Broad Institute), Yuichi Shiraishi, Ilya Shmulevich, Henrique C.S. Silveira(Hospital de Câncer de Barretos), Janae V. Simons, Payal Sipahimalani, Tara Skelly, Heidi J. Sofia, Matthew G. Soloway, Paul T. Spellman, Chip Stewart(University of North Carolina at Chapel Hill), Joshua M. Stuart, Qiang Sun, Jumpei Takeshita(Tokyo University of Science), Angela Tam, Donghui Tan, Roy Tarnuzzer, Kenji Tatsuno, Barry S. Taylor, Nina Thiessen, Eric Thompson, Vésteinn Thórsson(Institute for Systems Biology), William D. Travis(Memorial Sloan Kettering Cancer Center), Anne S. Tsao(The University of Texas MD Anderson Cancer Center), Kane Tse, Tohru Tsujimura, Federico Valdivieso, David Van Den Berg, Nico van Zandwijk, Umadevi Veluvolu, Luciano de Souza Viana, Douglas Voet, Yunhu Wan, Zhining Wang, Jing Wang, Joellen Weaver, John N. Weinstein, Daniel J. Weisenberger, Matthew D. Wilkerson, Lisa Wise, Ignacio I. Wistuba, Tina Wong, Ye Wu, Shogo Yamamoto, Liming Yang, Marjorie G. Zauderer(Memorial Sloan Kettering Cancer Center), Jean C. Zenklusen(National Cancer Institute), Jiashan Zhang, Hailei Zhang, Hongxin Zhang, Erik Zmuda
Cited by 617Open Access
Abstract
Abstract 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