Genetic predisposition for malignant mesothelioma: A concise review

Our plain-English summary of Genetic predisposition for malignant mesothelioma: A concise review, by M. Betti, A. Aspesi, M. Sculco, et al (Mutation Research. Reviews in Mutation Research, 2019).

The study

• Authors: M. Betti, A. Aspesi, M. Sculco, G. Matullo, C. Magnani, I. Dianzani
• Journal: Mutation Research. Reviews in Mutation Research
• Published: 2019;781:1-10
• Type of article: Review
• Cited by: 35 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is an aggressive cancer associated with asbestos exposure. Studies of familial malignant pleural mesothelioma (MPM) have suggested the existence of a genetic predisposition. Information on the role of genetic risk factors in the development of MM has been growing in the last years, and both low- and high-risk genetic factors have been identified, but genetic factors alone (without any exposure to asbestos or other mineral fibers) have never been shown to induce MM. Low-risk genetic factors have been identified in studies that systematically analyzed the whole genome. When considered alone these low-risk genetic factors carry a relative risk of MPM that is 10- to 15-fold lower than that carried by asbestos exposure; however, a large number of these factors in combination may increase the impact of asbestos exposure. High-risk genetic factors include truncating variants in the tumor suppressor BAP1 and in other tumor suppressor genes belonging to DNA repair pathways. Heterozygous germline variants in these genes may favor carcinogenesis if a second somatic variant occurs that impairs the wild-type allele. This impairment can cause genetic instability due to the suppression of a specific DNA repair pathway, and transformation. This genetic predisposition may have translational consequences, as it may predict patient response to drugs that induce tumor-specific synthetic lethality.

Copyright © 2019 Elsevier B.V. All rights reserved.

In plain English

This article is a review, not a new study. The authors searched PubMed up to July 2018 for English-language articles on inherited genetic risk factors for malignant mesothelioma and used 72. They described two genome-wide studies. One was Italian and carried out by their own group (407 pleural mesothelioma patients, 389 controls). The other was Australian (428 mesothelioma patients, 778 controls). These studies found common DNA variants with odds ratios from 0.54 to 2.37. The authors wrote that each variant alone carries a risk 10- to 15-fold lower than asbestos exposure, though several interacted with asbestos exposure. The most studied high-risk gene was BAP1. 182 families with BAP1 tumor predisposition syndrome had been identified, 77 with mesothelioma, but penetrance had not been calculated. Reviewed studies found that patients with truncating variants in BAP1 or other DNA repair genes had been exposed to less asbestos than other patients. The authors concluded that genetic factors alone, without exposure to asbestos or other mineral fibers, cannot cause mesothelioma. They also concluded that patients with truncating variants in certain DNA repair genes may respond to drugs that induce synthetic lethality.

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: Concise literature review of published studies (not original research)
• Who was studied: English-language articles in the NCBI PubMed database up to July 2018 on genetic risk factors for mesothelioma; 81 articles found, 72 used
• Exposure: Inherited (germline) DNA variants: low-risk common variants (SNPs) and high- or moderate-risk variants in BAP1 and other genes, mostly DNA repair genes, considered in relation to exposure to asbestos or other mineral fibers
• Main results:
  • Two genome-wide association studies were reviewed. The Italian study, by the authors' group, had 407 pleural mesothelioma patients and 389 controls. The Australian study had 428 mesothelioma patients and 778 controls. Together they identified different variants associated with mesothelioma, with odds ratios from 0.54 to 2.37.
  • Each low-risk variant alone was described as carrying a very low risk, 10- to 15-fold lower than that of asbestos exposure. In the Italian study, interaction with asbestos exposure was observed for several variants.
  • In the interaction analysis of the Italian study, six variants deviated from the additive model and four of these also deviated from the multiplicative model.
  • So far 182 families with BAP1 tumor predisposition syndrome have been identified, and studies have identified 77 families with mesothelioma.
  • The prevalence of BAP1 tumor predisposition syndrome among patients with familial pleural mesothelioma was between 6% and 7.7%, compared with less than 1% in sporadic cases.
  • In one reviewed study (Panou et al.) of 198 mesothelioma patients, 23 (12%) had germline mutations in cancer-susceptibility genes, and 83% of these were in DNA damage sensing and repair genes. That study reported such mutations were more common in peritoneal than in pleural mesothelioma.
  • Reviewed studies reported that patients with pathogenic truncating variants in BAP1 and other predisposing genes had been exposed to a lower amount of asbestos than patients without such variants. The difference was statistically significant.
  • In reviewed animal studies, Bap1+/- mice developed pleural mesothelioma when exposed to low amounts of asbestos.
• The authors' conclusion: The authors concluded that genetic factors alone, without exposure to asbestos or other mineral fibers, cannot cause mesothelioma. They also concluded that patients carrying these variants appear more sensitive to asbestos exposure, and that patients with truncating mutations in homologous recombination repair genes may respond to treatments that induce synthetic lethality.
• Limitations the authors state:
  • The penetrance of BAP1 tumor predisposition syndrome has not yet been calculated.
  • Quantified asbestos exposure was reported for only ten people with BAP1 tumor predisposition syndrome.
  • Follow-up data on BAP1 variant carriers are lacking.
  • More carriers of germline BAP1 variants need to be studied to rule out coincidental associations with some other tumor types.
  • Identifying low-risk genetic factors has had no clinical relevance so far.

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: Malignant Mesothelioma, Asbestos Exposure, Pleural Mesothelioma, Mineral Fiber, Relative Risk, BAP1, Tumor Suppressor Gene, Germline Mutation.

Related studies

• Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma — M. Betti, E. Casalone, et al. (2017)
• Are oestrogens and genetic predisposition etiologic factors in the development of clear cell carcinoma of the peritoneum? — R. Wuntakal, A. Lawrence (2013)
• Inherited Genetic Mutations and Polymorphisms in Malignant Mesothelioma: A Comprehensive Review — V. Panou, O.D. Røe (2020)
• A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma — K.A. Wadt, L.G. Aoude, et al. (2015)
• Genetic susceptibility to malignant mesothelioma and exposure to asbestos: the influence of the familial factor — D. Ugolini, M. Neri, et al. (2008)
• Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study — G. Matullo, S. Guarrera, et al. (2013)

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