The genetics of cancer heterogeneity and mesothelioma

Our plain-English summary of The genetics of cancer heterogeneity and mesothelioma, by L.R. Chirieac, R. Gill, R. Attanoos (Frontiers in Oncology, 2026).

The study

• Authors: L.R. Chirieac, R. Gill, R. Attanoos
• Journal: Frontiers in Oncology
• Published: 2026;16:1744382
• Type of article: Review
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Diffuse mesothelioma is an invasive cancer that originates from the cells in the smooth tissue lining (serosal membrane) that surrounds various body cavities. While most cases originate in the pleural lining of the thoracic cavity, a subset primarily involves the peritoneum or, rarely, the pericardium or the tunica vaginalis. Advances in molecular biology have established that cancer heterogeneity is common across a wide variety of histogenetically diverse neoplasms and that 'mesothelioma' as a disease is the same. It is increasingly evident that age, sex, and anatomic site-specific variations do exist which are often driven by recognized and recurrent mutations although a high degree of inter- and intra-tumor heterogeneity is present, and this is reviewed. Diverse patterns of disease exist with respect to clinical, radiologic, pathologic findings and these are driven by unique molecular events, the mechanisms and origin of which are increasingly determined to be due to stochastic events. Consequently, mesothelioma has not only considerable radiologic, macroscopic, and microscopic heterogeneity, but includes multiple distinct genetic entities. Most mesotheliomas are characterized by recurrent mutations in tumor suppressor genes and epigenetic regulators, including BAP1, NF2, TP53, SETD2, and other genes. Alterations are identified in multiple pathways in the regulation of cell-cycle, RNA processing, histone regulation, and cell growth. BAP1 is one of the most frequently altered genes and is activated by diverse mechanisms including BAP1 point mutations, copy number loss, inactivating structural rearrangements, and minute chromosomal deletions. Consistent with its histomorphologic heterogeneity, mesothelioma displays an impressive molecular diversity. Subsets of mesothelioma have unusual genetic alterations: genomic near-haploidization in rare pleural mesotheliomas with mutations in TP53 and/or SETDB1; oncogenic EWSR1-ATF1 fusion; ALK rearrangements in rare patients with peritoneal mesothelioma. In addition, germline mutations are present in a subset of patients with mesothelioma and primarily involve genes in the DNA repair and cell cycle regulation and are more common in patients who are young, with family history of mesothelioma, or with peritoneal mesothelioma. In this review, we discuss the considerable heterogeneity of mesothelioma, the diversity of radiologic and gross presentation, various morphologic features with distinctive histologies and ultimately, we individually describe subsets of tumors characterized by uncommon alterations such as germline mutations, genomic near-haploidization, ALK rearrangement, ATF1 rearrangement, or EWSR1::YY1 fusion, as well as the implications of these findings on the diagnostic workup.

Copyright © 2026 Chirieac, Gill and Attanoos.

In plain English

This article was a review. The authors described it as a systematic literature review of published studies found through PubMed, covering how mesothelioma varies in its clinical, imaging, microscopic and genetic features. It did not report new patient data of its own. Summarizing other studies, the authors reported that about 12-16% of people with mesothelioma carry pathogenic inherited (germline) mutations implicated in their cancer. These were more common in patients under 50, in peritoneal (25%) than in pleural (7%) mesothelioma, and in patients with no identifiable asbestos exposure. They described rare genetic subtypes. Near-haploid tumors made up about 3% of diffuse mesotheliomas. Tumors with gene fusions almost all arose in the peritoneum of young people with no history of asbestos exposure. Noting an evolving debate, the authors argued that mesotheliomas in people with inherited genetic syndromes can arise independently of asbestos in most settings. They concluded that unusual genetics should be considered in young patients, those with unusual family cancer histories, or those without significant asbestos exposure. They said the low incidence of mesothelioma limits the certainty of statistical analyses.

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: Review (described by the authors as a systematic literature review); no new patient data
• Who was studied: Published literature identified through PubMed searches: epidemiological cohorts of asbestos-exposed persons, cancer registries, case-control studies, case series and case reports. The number of studies reviewed is not stated.
• Exposure: No single exposure was studied. The review discussed genetic alterations and causes of mesothelioma, including commercial amphibole asbestos, non-asbestos mineral fibers, therapeutic radiation, chronic inflammatory conditions, and inherited (germline) mutations.
• Main results:
  • Citing other studies, the authors reported that approximately 12-16% of people with mesothelioma have specific pathogenic germline mutations that are implicated in the development of their cancer.
  • Citing another study, germline-mutation-associated mesotheliomas were reported as more common in patients under 50, in peritoneal (25%) versus pleural (7%) mesothelioma, and in patients with no identifiable asbestos exposure.
  • Citing earlier literature, the authors reported that amphibole asbestos exposure was historically found in 80-90% of male and 20-40% of female patients with pleural mesothelioma.
  • Citing earlier literature, the authors reported that fewer than 25% of peritoneal mesotheliomas in men and 15% in women are related to amphibole asbestos exposure.
  • Citing other cohorts, genomic near-haploidization was reported in approximately 3% of diffuse mesotheliomas.
  • Among the gene-fusion-associated mesotheliomas in the cited studies, almost all arose in the peritoneum, had epithelioid morphology, and occurred in young subjects with no history of asbestos exposure.
  • The authors noted a debate over the role of asbestos in people with inherited genetic syndromes. They argued that a female preponderance and the finding that half the tumors were peritoneal argue against sensitization to low-level asbestos.
  • The authors stated that mesotheliomas arising with inherited genetic syndromes can arise independently of asbestos in most settings.
  • Citing other studies, the authors reported that, compared with epithelioid mesothelioma, sarcomatoid mesothelioma has BAP1 alterations less often (about 50% versus about 20%) and CDKN2A/MTAP alterations more often (about 40% versus about 80%).
• The authors' conclusion: The authors concluded that unusual mesothelioma genetics (germline mutations, ALK rearrangement, near-haploidization, ATF1 rearrangements) should be considered in patients with unusual family cancer histories, in young patients, and in those without significant asbestos exposure.
• Limitations the authors state:
  • The low global incidence of mesothelioma gives statistical analyses a low degree of certainty.
  • Some genotype-phenotype associations remain unclear or speculative.
  • Treatment-response data for ALK-rearranged mesothelioma are anecdotal.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Peritoneum, Pericardium, Tunica Vaginalis, Neoplasm, Tumor Suppressor Gene, BAP1, Pleural Mesothelioma.

Related studies

• Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival — L. Quetel, C. Meiller, et al. (2020)
• Malignant Pleural Mesothelioma: Genetic and Microenviromental Heterogeneity as an Unexpected Reading Frame and Therapeutic Challenge — D.M. Abbott, C. Bortolotto, et al. (2020)
• Comparative analysis of genetic variants in pleural fluids and solid tissue biopsies of pleural mesothelioma patients: Implications for molecular heterogeneity assessment — R. Silvestri, F. Rea, et al. (2024)
• Clinicopathologic and genetic characteristics of young patients with pleural diffuse malignant mesothelioma — M. Vivero, R. Bueno, et al. (2018)
• Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity — L. Mangiante, N. Alcala, et al. (2023)
• Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma — C. Meiller, F. Montagne, et al. (2021)

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