The genetic susceptibility in the development of malignant pleural mesothelioma: somatic and germline variants, clinicopathological features and implication in practical medical/surgical care: a narrative review

Our plain-English summary of The genetic susceptibility in the development of malignant pleural mesothelioma: somatic and germline variants, clinicopathological features and implication in practical medical/surgical care: a narrative review, by M.T. Congedo, E.C. West, J. Evangelista, et al (Journal of Thoracic Disease, 2024).

The study

• Authors: M.T. Congedo, E.C. West, J. Evangelista, A.A. Mattingly, G. Calabrese, C. Sassorossi, A. Nocera, M. Chiappetta, S. Flamini, L. Abenavoli, S. Margaritora, L. Boccuto, F. Lococo
• Journal: Journal of Thoracic Disease
• Published: 2024;16(1):671-687
• Type of article: Review
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background And Objective: Malignant pleural mesothelioma (MPM) is a very aggressive primary tumor of the pleura whose main risk factor is exposure to asbestos. However, only a minority of exposed people develops MPM and the incidence of MPM cases without an apparent association with asbestos exposure has been increasing in recent years, suggesting that genetic predisposing factors may play a crucial role. In addition, several studies reported familial cases of MPM, suggesting that heredity may be an important and underestimated feature in MPM development. Several candidate genes have been associated with a predisposition to MPM and most of them play a role in DNA repair mechanisms: overall, approximately 20% of MPM cases may be related to genetic predisposition. A particular category of patients with high susceptibility to MPM is represented by carriers of pathogenic variants in the BAP1 gene. Germline variants in BAP1 predispose to the development of MPM following an autosomal dominant pattern of inheritance in the familial cases. MPMs in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. In the present narrative review, we presented a comprehensive overview of genetic susceptibility in the development of MPM.

Methods: The narrative review is based on a selective literature carried out in PubMed in 2023. Inclusion criteria were original articles in English language, and clinical trials (randomized, prospective, or retrospective).

Key Content And Findings: We summarized the somatic and germline variants and the differences in terms of clinicopathological features and prognosis between gene-related MPM (GR-MPM) and asbestos-related MPM (AR-MPM). We also discussed the indications for screening, genetic testing, and surveillance of patients with BAP1 germline variants.

Conclusions: In this narrative review, we have emphasized that the BAP1 gene's harmful germline variations are inherited in an autosomal dominant manner in familial cases. MPMs in individuals with these variations are less severe, and their medical care necessitates a collaborative effort. Additionally, we have outlined the current therapeutic prospects for MPM, including the possibility of gene-specific therapy, which is currently promising but still requires clinical validation.

2024 Journal of Thoracic Disease. All rights reserved.

In plain English

This article was a narrative review, not a new study. The authors searched PubMed on January 2, 2023 for English-language original articles and clinical trials from 2001 to 2023 on the genetics of malignant pleural mesothelioma. Two authors screened abstracts. The number of articles included was not reported. The review described tumor (somatic) and inherited (germline) gene variants, especially in the BAP1 gene, and compared gene-related with asbestos-related pleural mesothelioma. In one summarized study of 174 people with germline BAP1 variants, 22% developed malignant mesothelioma. Another reported overall survival of 60 months in BAP1 variant carriers versus 17 months in non-carriers, all with previous asbestos exposure. The authors stated that about 20% of cases may relate to genetic predisposition. They concluded that gene-related cases occurred in younger patients with no sex predominance, often without symptoms and at an early stage. They also concluded that pathogenic germline BAP1 variants are inherited in an autosomal dominant pattern in familial cases, and that gene-targeted therapy was promising but not yet validated. They noted that only small cohorts of germline variant carriers had been evaluated.

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: Narrative review of published literature identified by a PubMed search
• Who was studied: Published original articles and clinical trials in English (January 1, 2001 to January 1, 2023) on malignant pleural mesothelioma genetics. A summary table listed 12 genetic studies of adult patients. The total number of included articles was not reported.
• Exposure: Germline and somatic genetic variants, mainly in BAP1 and also in genes such as NF2, TP53, CDKN2A and SETD2. These were compared with asbestos exposure. No asbestos fiber types were named.
• Main results:
  • In a cited study by Rai et al. of 174 patients with germline BAP1 variants, 75% developed at least one of five major malignancies, including malignant mesothelioma in 22%.
  • In a cited observational study, overall survival was 60 months in patients carrying BAP1 variants versus 17 months in patients without the variant. Both groups had previous asbestos exposure.
  • In a cited study by Pastorino and colleagues, 43 of 79 patients had deleterious germline BAP1 variants. These patients had a median age at diagnosis of 54 years and a median survival of 5 years. Among patients with germline variants, only 28% reported possible asbestos exposure.
  • The review's comparison table gave a mean age at presentation of 72.3 years for asbestos-related cases and 56.3 years for gene-related cases. The male-to-female ratio was 5:1 for asbestos-related cases and 1:1 for gene-related cases.
  • In a cited phase 2 trial of tazemetostat in patients with BAP1-inactivated mesothelioma, the disease control rate at week 12 was 54% (95% CI 42 to 67%; 33 of 61 patients).
  • In a cited phase 2 olaparib trial, the four patients with germline BAP1 mutations had a median progression-free survival of 2.3 months (95% CI 1.3 to 3.6) and a median overall survival of 4.6 months (95% CI 3.1 to 4.9).
• The authors' conclusion: The authors concluded the following. About 20% of cases may be related to genetic predisposition. Gene-related cases occurred in younger patients with no gender predilection, without symptoms, and at an early stage. Pathogenic germline BAP1 variants segregate in an autosomal dominant pattern in familial cases, and the resulting mesotheliomas are less aggressive and need multidisciplinary management. Gene-targeted therapy is promising but not yet validated.
• Limitations the authors state:
  • The rarity of the disease limits sample sizes in available genetic data.
  • Defining the genes and mechanisms involved still requires more primary research.
  • Only small cohorts of patients carrying different germline variants have been evaluated.
  • There is a lack of large studies on mesothelioma incidence among carriers of BAP1 germline variants.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Germline Mutation, Pleura, Asbestos Exposure, BAP1, Multidisciplinary Team, Genetic Counseling, Pathology.

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