Integrative Molecular Characterization of Malignant Pleural Mesothelioma

被引：456

作者：

Hmeljaki, Jutija ^{[1
,2
]}

Sanchez-Vega, Francisco ^{[3
]}

Hoadley, Katherine A. ^{[4
]}

Shih, Juliann ^{[5
,6
]}

Stewart, Chip ^{[4
]}

Heiman, David ^{[4
]}

Tarpeyg, Patrick ^{[7
]}

Danitova, Ludmila ^{[8
]}

Drill, Esther ^{[9
]}

Gibb, Ewan A. ^{[10
]}

Bowlby, Reanne ^{[11
]}

Kanchil, Rupa ^{[12
]}

Osmanbeyoglull, Hatice U. ^{[13
]}

Sekido, Yoshitaka ^{[14
]}

Takeshita, Jumpei ^{[15
]}

Newton, Yulia ^{[16
,17
]}

Graim, Kiley ^{[16
,17
]}

Gupta, Manaswi ^{[5
,6
]}

Gaylg, Cart M. ^{[18
]}

Diaol, Lixia ^{[12
]}

Gibbs, David L. ^{[19
]}

Thorsson, Vesteinn ^{[19
]}

Lype, Lisa ^{[19
]}

Kanthetir, Havish ^{[20
]}

Severson, David T. ^{[21
,22
]}

Ravegnini, Gloria ^{[23
]}

Desrneules, Patrice ^{[24
]}

Jungbluth, Achim A. ^{[25
]}

Travis, William D. ^{[25
]}

Dacic, Sanja ^{[26
]}

Chirieac, Lucian R. ^{[27
]}

Galateau-Salle, Francoise ^{[28
]}

Fujimoto, Junya ^{[29
]}

Husain, Aliya N. ^{[30
]}

Silveira, Henrique C. ^{[31
]}

Rusch, Valerie W. ^{[32
]}

Rintoul, Robert C. ^{[33
]}

Pass, Harvey ^{[34
]}

Kindler, Heciy ^{[35
,36
]}

Zauderer, Marjorie G. ^{[37
]}

Kwiatkowski, David J. ^{[38
]}

Bueno, Raphael ^{[21
,22
]}

Tsaols, Anne S. ^{[18
]}

Creaney, Jenette ^{[39
]}

Lichtenberg, Tara ^{[40
]}

Leraas, Kristen ^{[40
]}

Bowen, Jay ^{[40
]}

Felau, Ina ^{[41
]}

Zenklusen, Jean Claude ^{[41
]}

Akbanil, Rehan ^{[12
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Pathol & Human Oncol, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Pathogenesis Program, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Marie Josee & Henry R Kravis Ctr Mol Oncol, New York, NY 10065 USA

[4] Univ N Carolina, Dept Genet, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27515 USA

[5] MIT, Eli & Edythe L Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[6] Harvard Univ, Cambridge, MA 02138 USA

[7] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton, Cambs, England

[8] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA

[9] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA

[10] GenomeDx Biosci, Vancouver, BC, Canada

[11] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada

[12] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[13] Mem Sloan Kettering Canc Ctr, Computat Syst Biol, New York, NY 10065 USA

[14] Aichi Canc Ctr Res Inst, Div Canc Biol, Nagoya, Aichi, Japan

[15] Univ Tokyo, Genome Sci Div, Tokyo, Japan

[16] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA

[17] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA

[18] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA

[19] Inst Syst Biol, Seattle, WA USA

[20] Univ Texas Dallas, Richardson, TX 75083 USA

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

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

[23] Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy

[24] Quebec Heart & Lung Inst, Dept Pathol, Quebec City, PQ, Canada

[25] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[26] Univ Pittsburgh, Dept Pathol, Med Ctr, Pittsburgh, PA USA

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

[28] Canc Ctr Leon Berard, MESOPATH, Lyon, France

[29] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

[30] Univ Chicago, Dept Pathol, 5841 S Maryland Ave, Chicago, IL 60637 USA

[31] Barretos Canc Hosp, Mol Oncol Res Ctr, Sao Paulo, Brazil

[32] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA

[33] Univ Cambridge, Dept Oncol, Cambridge, England

[34] NYU, Dept Cardiothorac Surg, Langone Med Ctr, New York, NY USA

[35] Univ Chicago, Med Ctr, Dept Med, Sect Hematol Oncol, Chicago, IL 60637 USA

[36] Biol Sci, Chicago, IL USA

[37] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[38] Brigham & Womens Hosp, Div Pulm Med, 75 Francis St, Boston, MA 02115 USA

[39] Univ Western Australia, Sch Med & Pharmacol, Nedlands, WA, Australia

[40] Nationwide Childrens Hosp, Res Inst, Columbus, OH USA

[41] NCI, Bethesda, MD 20892 USA

来源：

CANCER DISCOVERY | 2018年 / 8卷 / 12期

基金：

美国国家卫生研究院;

关键词：

IMMUNE-CHECKPOINT; TUMOR-SUPPRESSOR; WHOLE-EXOME; CANCER; BAP1; GENE; CELLS; EXPRESSION; MUTATIONS; DELETION;

D O I：

10.1158/2159-8290.CD-18-0804

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. (C) 2018 AACR.

引用

页码：1548 / 1565

页数：18

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