Isolated BAP1 Genomic Alteration in Malignant Pleural Mesothelioma Predicts Distinct Immunogenicity with Implications for Immunotherapeutic Response

Our plain-English summary of Isolated BAP1 Genomic Alteration in Malignant Pleural Mesothelioma Predicts Distinct Immunogenicity with Implications for Immunotherapeutic Response, by H.U. Osmanbeyoglu, D. Palmer, A. Sagan, et al (Cancers, 2022).

The study

• Authors: H.U. Osmanbeyoglu, D. Palmer, A. Sagan, E. Sementino, M.J. Becich, J.R. Testa
• Journal: Cancers
• Published: 2022;14(22)
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM), an aggressive cancer of the mesothelial cells lining the pleural cavity, lacks effective treatments. Multiple somatic mutations and copy number losses in tumor suppressor genes (TSGs) BAP1, CDKN2A/B, and NF2 are frequently associated with MPM. The impact of single versus multiple genomic alterations of TSG on MPM biology, the immune tumor microenvironment, clinical outcomes, and treatment responses are unknown. Tumors with genomic alterations in BAP1 alone were associated with a longer overall patient survival rate compared to tumors with CDKN2A/B and/or NF2 alterations with or without BAP1 and formed a distinct immunogenic subtype with altered transcription factor and pathway activity patterns. CDKN2A/B genomic alterations consistently contributed to an adverse clinical outcome. Since the genomic alterations of only BAP1 was associated with the PD-1 therapy response signature and higher LAG3 and VISTA gene expression, it might be a candidate marker for immune checkpoint blockade therapy. Our results on the impact of TSG genotypes on MPM and the correlations between TSG alterations and molecular pathways provide a foundation for developing individualized MPM therapies.

In plain English

This study re-analyzed public data on malignant pleural mesothelioma tumors: 86 from The Cancer Genome Atlas (TCGA), with genetic, gene-activity and clinical data, and 61 from MSK-IMPACT, lacking gene-activity data. Asbestos exposure was not studied. The authors grouped tumors by mutations and/or deletions in three tumor suppressor genes, BAP1, CDKN2A/B and NF2, into eight groups. In TCGA, tumors with a change in BAP1 alone were associated with longer survival than other tumors (median 32.28 months; hazard ratio 0.38, 95% CI 0.17 to 0.83). In MSK-IMPACT the hazard ratio was 0.47 (95% CI 0.19 to 1.19, p = 0.112). CDKN2A/B changes were associated with poorer survival in both collections. Using TCGA gene-activity patterns, the authors predicted treatment response; these were not actual treatment outcomes. In TCGA, BAP1-only tumors fell only in a group predicted to respond to anti-PD-1 immunotherapy, had higher expression of immune checkpoint genes LAG3 and VISTA, and showed higher estimated interferon signaling. The authors named small cohort size as a major limitation. They concluded that a BAP1-only change could be a candidate marker for selecting patients for immune checkpoint therapy.

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: Computational (in silico) analysis of publicly available tumor genetic and gene-expression datasets, with survival analysis using Kaplan-Meier and Cox models
• Who was studied: Malignant pleural mesothelioma tumors from two existing datasets. TCGA (n = 86) consisted of surgical specimens from untreated tumors and had RNA-sequencing (gene-activity) data. MSK-IMPACT (n = 61) was a mix of resection samples and specimens from tumors that had received pemetrexed-based therapy and/or checkpoint inhibitors, and had no parallel RNA-sequencing data. Tumors were mostly epithelioid. No locations or dates of diagnosis are given.
• Exposure: Not asbestos. The factor studied was tumor genetic changes (deletions and/or mutations) in the tumor suppressor genes BAP1, CDKN2A/B and NF2, alone or in combination, sorted into eight groups. Asbestos is mentioned only as background in the introduction.
• Main results:
  • TCGA tumors with an alteration in BAP1 only were significantly associated with longer survival compared with other tumors (32.28 months; HR 0.38, 95% CI 0.17 to 0.83; p = 0.016).
  • MSK-IMPACT tumors with an alteration in BAP1 only: 21.14 months; HR 0.47 (95% CI 0.19 to 1.19); p = 0.112.
  • TCGA tumors with alterations in all three genes (BAP1, NF2 and CDKN2A/B) were associated with poor survival (8.32 months; HR 2.62, 95% CI 1.35 to 5.07; p = 0.004).
  • When the three genes were modeled without interactions, tumors with CDKN2A/B alterations were associated with poor survival in TCGA (HR 3.23, 95% CI 1.89 to 5.51, p = 2 times 10 to the minus 5) and in MSK-IMPACT (HR 5.31, 95% CI 1.70 to 16.57, p = 0.004).
  • In the same model, BAP1 and NF2 alterations had no significant effect on survival.
  • TCGA only, using gene-expression signatures rather than actual treatment outcomes: on average, tumors with CDKN2A/B alteration scored as more resistant to pemetrexed and palbociclib, while tumors with only BAP1 loss or with BAP1 and NF2 losses scored as more sensitive.
  • TCGA: mRNA expression of the immune checkpoint genes LAG3 and VISTA was higher in BAP1-only tumors. PD-1, PD-L1, TIGIT and CTLA4 mRNA levels were not associated with gene-alteration group.
  • TCGA: using a published gene signature for anti-PD-1 response, BAP1-only tumors appeared only in the predicted anti-PD-1-responsive subgroup (p = 0.0032).
  • TCGA: BAP1-only tumors had an estimated lower proportion of B cells (p = 0.016) and a higher proportion of natural killer cells (p = 0.031) than other groups. No difference was seen for CD8+ T cells.
  • TCGA: BAP1-only tumors were associated with increased interferon-alpha and interferon-beta signaling activity, as inferred from gene-expression data.
• The authors' conclusion: The authors concluded that, despite the limitations, an isolated BAP1 alteration could be a candidate biomarker for selecting patients for immune checkpoint blockade therapies.
• Limitations the authors state:
  • Small cohort size.
  • The share of tumors in each gene-alteration group differed between TCGA and MSK-IMPACT. The authors suggest this may reflect the different sequencing methods (whole-exome sequencing versus a targeted screen).

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Pleural Mesothelioma, Mesothelial Cells, Pleural Cavity, Somatic Mutation, Tumor Suppressor Gene, CDKN2A, Tumor Microenvironment.

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