Dataset Information

Integrative Molecular Characterization of Malignant Pleural Mesothelioma.

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.

SUBMITTER: Hmeljak J

PROVIDER: S-EPMC6310008 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Integrative Molecular Characterization of Malignant Pleural Mesothelioma.

Hmeljak Julija J Sanchez-Vega Francisco F Hoadley Katherine A KA Shih Juliann J Stewart Chip C Heiman David D Tarpey Patrick P Danilova Ludmila L Drill Esther E Gibb Ewan A EA Bowlby Reanne R Kanchi Rupa R Osmanbeyoglu Hatice U HU Sekido Yoshitaka Y Takeshita Jumpei J Newton Yulia Y Graim Kiley K Gupta Manaswi M Gay Carl M CM Diao Lixia L Gibbs David L DL Thorsson Vesteinn V Iype Lisa L Kantheti Havish H Severson David T DT Ravegnini Gloria G Desmeules Patrice P Jungbluth Achim A AA Travis William D WD Dacic Sanja S Chirieac Lucian R LR Galateau-Sallé Françoise F Fujimoto Junya J Husain Aliya N AN Silveira Henrique C HC Rusch Valerie W VW Rintoul Robert C RC Pass Harvey H Kindler Hedy H Zauderer Marjorie G MG Kwiatkowski David J DJ Bueno Raphael R Tsao Anne S AS Creaney Jenette J Lichtenberg Tara T Leraas Kristen K Bowen Jay J Felau Ina I Zenklusen Jean Claude JC Akbani Rehan R Cherniack Andrew D AD Byers Lauren A LA Noble Michael S MS Fletcher Jonathan A JA Robertson A Gordon AG Shen Ronglai R Aburatani Hiroyuki H Robinson Bruce W BW Campbell Peter P Ladanyi Marc M

Cancer discovery 20181015 12

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-checkp ...[more]

PMID: 30322867

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Project description:Malignant pleural mesothelioma (MPM) is a highly lethal, poorly understood neoplasm that is typically associated with asbestos exposure. We performed transcriptional profiling using high-density oligonucleotide microarrays containing approximately 22,000 genes to elucidate potential molecular and pathobiological pathways in MPM using discarded human MPM tumor specimens (n=40), normal lung specimens (n=4), normal pleura specimens (n=5), and MPM and SV40-immortalized mesothelial cell lines (n=5). In global expression analysis using unsupervised clustering techniques, we found two potential subclasses of mesothelioma which correlate loosely with tumor histology. We also identified sets of genes with expression levels that distinguish between multiple tumor subclasses, normal and tumor tissues, and tumors with different morphologies. Microarray gene expression data were confirmed using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and protein analysis for three novel candidate oncogenes (NME2, CRI1, and PDGFC) and one candidate tumor suppressor (GSN). Finally, we used bioinformatics tools (i.e. software) to create and explore complex physiological pathways that may be relevant in mesothelioma tumorigenesis, pathobiology, or both. Tissues and cell lines profiled using microarrays. Discarded MPM surgical specimens (n=40), normal pleura specimens (n=5), and normal lung specimens (n=4) were freshly collected (and snap frozen) from patients who underwent surgery at Boston's Brigham and Women's Hospital (BWH) between October 1998 and August 2000. All of these patients underwent extrapleural pneumonectomy with heated intra-pleural cisplatin chemotherapy delivered after the specimens were removed. All normal specimens were obtained from patients who were never diagnosed with MPM. Two human MPM cell lines (MS589 and MS428) were kindly provided by Jonathan A. Fletcher, M.D., Department of Pathology, BWH. The JMN1B MPM cell line19,20 has been described previously. The SV40-immortalized, non-tumorigenic mesothelial cell line (Met-5A)21 and the MPM cell line MSTO-211H22 were purchased from the American Type Culture Collection. Normal tissues were obtained from additional consented patients undergoing treatment for diseases other than MPM. All MPM samples used in these studies contained relatively pure tumor (greater than 50% tumor cells per high power field examined in a section adjacent to the tissue used). The microscopic slides from the patients' resection specimens were reviewed by one of the authors (J.G.), and the diagnosis and histologic subclassification of MPM confirmed in all cases. Linked clinical and pathological data were obtained for all patients who contributed tumor specimens. Specimens and data were rendered anonymous to protect patient confidentiality. Studies utilizing human tissues were approved by and conducted in accordance with the policies of the Institutional Review Board at BWH.

Dataset Information

Integrative Molecular Characterization of Malignant Pleural Mesothelioma.

Publications

Integrative Molecular Characterization of Malignant Pleural Mesothelioma.

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