Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Our plain-English summary of Integrative Molecular Characterization of Malignant Pleural Mesothelioma, by J. Hmeljak, F. Sanchez-Vega, K.A. Hoadley, et al (Cancer Discovery, 2018).

The study

• Authors: J. Hmeljak, F. Sanchez-Vega, K.A. Hoadley, J. Shih, C. Stewart, D. Heiman, P. Tarpey, L. Danilova, E. Drill, E.A. Gibb, R. Bowlby, R. Kanchi, H.U. Osmanbeyoglu, Y. Sekido, J. Takeshita, Y. Newton, K. Graim, M. Gupta, C.M. Gay, L. Diao, D.L. Gibbs, V. Thorsson, L. Iype, H. Kantheti, D.T. Severson, G. Ravegnini, P. Desmeules, A.A. Jungbluth, W.D. Travis, S. Dacic, L.R. Chirieac, F. Galateau-Sallé, J. Fujimoto, A.N. Husain, H.C. Silveira, V.W. Rusch, R.C. Rintoul, H. Pass, H. Kindler, M.G. Zauderer, D.J. Kwiatkowski, R. Bueno, A.S. Tsao, J. Creaney, T. Lichtenberg, K. Leraas, J. Bowen, TCGA Research Network, I. Felau, J.C. Zenklusen, R. Akbani, A.D. Cherniack, L.A. Byers, M.S. Noble, J.A. Fletcher, A.G. Robertson, R. Shen, H. Aburatani, B.W. Robinson, P. Campbell, M. Ladanyi
• Journal: Cancer Discovery
• Published: 2018;8(12):1548-1565
• Cited by: 521 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

©2018 American Association for Cancer Research.

In plain English

As part of The Cancer Genome Atlas (TCGA), the authors profiled 74 samples of malignant pleural mesothelioma (MPM) from patients with no prior systemic therapy (82% male, median age 64, 70% epithelioid). Asbestos exposure history was positive in 62%, negative in 18% and otherwise unknown. Mutation patterns did not differ significantly between cases with and without known asbestos exposure (P=0.3), a negative finding the authors said should be viewed with caution. BAP1 alterations were found in 57% of samples, and loss of CDKN2A was associated with shorter survival. Among 154 tumors from TCGA and a Japanese cohort, 5 (3.2%) had lost one copy of nearly all chromosomes and carried SETDB1 alterations, which the authors defined as a new subtype. Four molecular clusters differed in survival but showed no significant correlation with asbestos exposure history. The immune-checkpoint gene VISTA was expressed in MPM at higher levels than in any other TCGA tumor type analyzed, and in two stained epithelioid cases its protein appeared in tumor cells. The authors concluded this provides a rationale for trials of anti-VISTA therapy in epithelioid MPM.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Multi-platform genomic (molecular profiling) study of tumor samples, part of The Cancer Genome Atlas (TCGA), with comparison and validation in other published or independent cohorts
• Who was studied: 74 samples of primary malignant pleural mesothelioma from patients with no prior systemic therapy. The cohort was 82% male, median age 64, and 70% epithelioid. Additional cohorts were also used: 80 samples from a Japanese International Cancer Genome Consortium (ICGC) cohort, 16 near-haploid cases from an independent cytogenetic series, and two published validation cohorts (211 and 52 MPM). Places and dates of sample collection are not given in the main text.
• Exposure: Asbestos exposure history only, recorded as yes or no: positive in 62%, negative in 18%, and unavailable or unknown in the remainder. No fiber types, products, jobs or doses are given. Smoking history was also compared.
• Main results:
  • The mutational spectrum and local sequence context did not differ significantly between cases with and without known asbestos exposure (chi-squared, P=0.3).
  • Mutations in the five significantly mutated genes (BAP1, NF2, TP53, LATS2, SETD2) showed no associations with histories of asbestos exposure or smoking.
  • The overall prevalence of BAP1 alterations in the TCGA cohort was 57%.
  • No germline (inherited) BAP1 mutations were identified in this cohort.
  • CDKN2A deletions (deep, likely homozygous) were found in 36 (49%) samples, and losses in 5 (7%).
  • Loss of CDKN2A was strongly associated with shorter overall survival (Cox proportional hazards, P=7.3x10-6). No correlation with overall survival was observed for BAP1 status.
  • Genomic near-haploidization was found in 3 TCGA cases and 2 Japanese ICGC cases, a combined prevalence of 5/154 (3.2%). All 5 had inactivating mutations in, or homozygous deletion of, SETDB1, and 4 of 5 had TP53 driver mutations.
  • Among the combined set of 21 near-haploid MPM, most patients were female (M:F=1:4). In the overall TCGA-ICGC cohort, males predominated (M:F>4:1; p<0.01).
  • Integrative clustering identified four subtypes whose survival differed significantly (P<0.0001 for either algorithm).
  • The survival difference between clusters remained significant (P=0.008) after adjusting for histology and CDKN2A homozygous deletion.
  • The clusters showed no significant correlation with clinical variables including asbestos exposure history or smoking.
  • VISTA mRNA expression was higher in MPM than in any other TCGA tumor type analyzed. Within MPM, it was highest in the epithelioid subtype.
  • In immunohistochemical staining of two epithelioid TCGA cases, VISTA protein was present in tumor cells, not only in infiltrating immune cells. It was also present in normal and reactive mesothelium.
  • An analysis for genomically integrated viral sequences, including SV40, was negative.
• The authors' conclusion: The authors concluded that their findings provide both a rationale and a candidate biomarker for clinical trials of emerging anti-VISTA therapy in epithelioid MPM.
• Limitations the authors state:
  • The authors said the negative finding on asbestos exposure and mutational spectrum should be viewed with caution given the limitations of the dataset.
  • In the smaller Lopez-Rios validation cohort, patient numbers were too small to split by histology.
  • Cytogenetic analysis can only identify near-haploid cases that have not undergone genome duplication.
  • The survival of the near-haploid subset and its association with asbestos exposure, which the authors said so far appears weak or unclear, still need to be defined by systematic clinical studies.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, BAP1, Histology, Epithelioid, Immunotherapy.

Related studies

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• Molecular characterization of localized pleural mesothelioma — Y.P. Hung, F. Dong, et al. (2020)
• Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas — H.C. Kang, H.K. Kim, et al. (2016)
• Challenges and controversies in the diagnosis of malignant mesothelioma: Part 2. Malignant mesothelioma subtypes, pleural synovial sarcoma, molecular and prognostic aspects of mesothelioma, BAP1, aquaporin-1 and microRNA — D.W. Henderson, G. Reid, et al. (2013)
• BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas — N. Leblay, F. Leprêtre, et al. (2017)
• Sarcomatoid Mesothelioma: A CDKN2A molecular analysis of 53 cases with immunohistochemical correlation with BAP1 — M. Zaleski, N. Kalhor, et al. (2020)

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