Genomic landscape of pleural and peritoneal mesothelioma tumours

Our plain-English summary of Genomic landscape of pleural and peritoneal mesothelioma tumours, by S. Hiltbrunner, Z. Fleischmann, E.S. Sokol, et al (British Journal of Cancer, 2022).

The study

• Authors: S. Hiltbrunner, Z. Fleischmann, E.S. Sokol, M. Zoche, E. Felley-Bosco, A. Curioni-Fontecedro
• Journal: British Journal of Cancer
• Published: 2022;127(11):1997-2005
• Cited by: 106 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural and peritoneal mesotheliomas are rare malignancies with unacceptable poor prognoses and limited treatment options. The genomic landscape is mainly characterised by the loss of tumour suppressor genes and mutations in DNA repair genes. Currently, data from next-generation sequencing (NGS) of mesothelioma tumours is restricted to a limited number of cases; moreover, data comparing molecular features of mesothelioma from the pleural and peritoneal origin with NGS are lacking.

Methods: We analysed 1113 pleural mesothelioma and 355 peritoneal mesothelioma samples. All tumours were sequenced with the FoundationOne® or FoundationOne®CDx assay for detection of substitutions, insertion-deletions, copy-number alterations and selected rearrangements in at least 324 cancer genes.

Results: This analysis revealed alterations in 19 genes with an overall prevalence of at least 2%. Alterations in BAP1, CDKN2A, CDKN2B, NF2, MTAP, TP53 and SETD2 occurred with a prevalence of at least 10%. Peritoneal, compared to pleural mesothelioma, was characterised by a lower prevalence of alterations in CDKN2A, CDKN2B and MTAP. Moreover, we could define four distinct subgroups according to alterations in BAP1 and CDKN2A/B. Alterations in Hedgehog pathway-related genes (PTCH1/2 and SUFU) and Hippo pathway-related gene (NF2) as well as KRAS, EGFR, PDGFRA/B, ERBB2 and FGFR3 were detected in both cohorts.

Conclusion: Here, we report the molecular aberrations from the largest cohort of patients with mesothelioma. This analysis identified a proportion of patients with targetable alterations and suggests that molecular profiling can identify new treatment options for patients with mesothelioma.

© 2022. The Author(s).

In plain English

The authors analysed genetic test results from 1113 pleural mesothelioma and 355 peritoneal mesothelioma tumour samples from patients in the United States, sequenced as part of routine care through December 2020 using tests covering at least 324 cancer genes. Alterations in 19 genes appeared in at least 2% of tumours. Across all samples the most common were in BAP1 (45.1%), CDKN2A (42.2%), CDKN2B (36.0%) and NF2 (31.3%). Deletions in CDKN2A/B were more frequent in pleural than in peritoneal tumours: CDKN2A was altered in 48.2% of pleural and 25.9% of peritoneal tumours. The authors sorted tumours into four subgroups according to changes in BAP1 and CDKN2A/B. Rare alterations that drugs can target, including in KRAS, EGFR and ALK, were found in both groups. The article reported no asbestos exposure data. Asbestos appeared as background drawn from other studies. In the discussion, the authors also offered it as a possible explanation for the pleural–peritoneal difference. They called the lack of clinical data on histology, outcome and treatment a major limitation, and concluded that molecular analysis for mesothelioma should be implemented.

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: Retrospective analysis of tumour genomic profiling (next-generation sequencing) results
• Who was studied: Tumour samples from 1113 patients with pleural mesothelioma and 355 with peritoneal mesothelioma in the United States, sequenced through December 2020 as part of routine clinical care. Testicular, pericardial and unspecified mesotheliomas were excluded.
• Exposure: Not measured. The study examined genetic alterations in tumour tissue, not asbestos or other exposures. In the discussion the authors suggested, as a possible explanation for the pleural–peritoneal difference, that chromosome arm deletions are associated with asbestos exposure. This was not tested in the study.
• Main results:
  • In the total cohort, alterations in 19 genes had at least 2% prevalence. The most common were BAP1 (45.1%), CDKN2A (42.2%), CDKN2B (36.0%), NF2 (31.3%), MTAP (27.3%), TP53 (17.3%) and SETD2 (10.2%).
  • In pleural mesothelioma the five most frequently altered genes were CDKN2A (48.2%), BAP1 (45.0%), CDKN2B (42.2%), NF2 (32.8%) and MTAP (32.3%).
  • In peritoneal mesothelioma the five most frequently altered genes were BAP1 (47.9%), NF2 (26.5%), CDKN2A (25.9%), CDKN2B (19.5%) and PBRM1 (15.8%).
  • Deletions in CDKN2A/B were more frequent in pleural than in peritoneal mesothelioma.
  • Tumours were sorted into four subgroups by alterations in BAP1 and CDKN2A/B. In pleural mesothelioma, Group 4 (neither) had a significantly higher prevalence of TP53 alterations (30.3%) than the whole pleural group.
  • High tumour mutational burden (at least 10 mutations per megabase) was rare: 15 (1.35%) pleural and 5 (1.41%) peritoneal patients.
  • ALK rearrangements and short variant alterations were found in 0.36% of pleural and 1.13% of peritoneal mesothelioma patients. Ten patients had the KRAS G12C mutation.
• The authors' conclusion: The authors concluded that molecular analysis for mesothelioma should be implemented, because it identified a proportion of patients with targetable alterations.
• Limitations the authors state:
  • There was no matching clinical data on histology, outcome, treatment allocation or response to treatment, because the analysis was retrospective.
  • So few cases had increased mutational burden that the authors could not tell whether co-occurring alterations were truly enriched and functionally important.

Topics

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

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Next-Generation Sequencing (NGS), Mesothelioma, Pleural Mesothelioma, BAP1, CDKN2A, MTAP, EGFR.

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