Inherited Genetic Mutations and Polymorphisms in Malignant Mesothelioma: A Comprehensive Review

Our plain-English summary of Inherited Genetic Mutations and Polymorphisms in Malignant Mesothelioma: A Comprehensive Review, by V. Panou, O.D. Røe (International Journal of Molecular Sciences, 2020).

The study

• Authors: V. Panou, O.D. Røe
• Journal: International Journal of Molecular Sciences
• Published: 2020;21(12)
• Type of article: Review
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is mainly caused by air-born asbestos but genetic susceptibility is also suspected to be a risk factor. Recent studies suggest an increasing number of candidate genes that may predispose to MM besides the well-characterized BRCA1-associated protein-1 gene. The aim of this review is to summarize the most important studies on germline mutations for MM. A total of 860 publications were retrieved from Scopus, PubMed and Web of Science, of which 81 met the inclusion criteria and were consider for this review. More than 50% of the genes that are reported to predispose to MM are involved in DNA repair mechanisms, and the majority of them have a role in the homologous recombination pathway. Genetic alterations in tumor suppressor genes involved in chromatin, transcription and hypoxia regulation have also been described. Furthermore, we identified several single nucleotide polymorphisms (SNPs) that may promote MM tumorigenesis as a result of an asbestos-gene interaction, including SNPs in DNA repair, carcinogen detoxification and other genes previously associated with other malignancies. The identification of inherited mutations for MM and an understanding of the underlying pathways may allow early detection and prevention of malignancies in high-risk individuals and pave the way for targeted therapies.

In plain English

This article was a review of published research on inherited (germline) genetic changes that may make people more likely to develop malignant mesothelioma. The authors searched Scopus, PubMed and Web of Science for English-language studies in humans from January 2011 to February 2020 and manually reviewed 81 articles. The authors reported that more than half of the genes described in the literature as predisposing to mesothelioma are involved in DNA repair. BAP1 was the most well-characterized gene. Reviewed studies reported BAP1 mutations in 0 to 7% of mesothelioma cases, rising to as much as 20% in familial cases. Reviewed studies also reported that pleural mesothelioma patients with inherited mutations in these genes tended to survive longer than those without. The authors summarized studies of common gene variants (SNPs) and noted that two genome-wide studies gave no compelling evidence that the identified SNPs can cause mesothelioma without asbestos exposure. The authors concluded that there are only a few large studies, and that genetic testing of high-risk individuals may help early cancer detection.

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: Literature review (described by the authors as a comprehensive review) of studies on inherited genetic mutations and polymorphisms in malignant mesothelioma
• Who was studied: Published articles on human subjects in English, identified by searching Scopus, PubMed and Web of Science from January 2011 to February 2020. Articles on somatic (tumor-only) mutations were excluded, as were abstracts, case reports, conference presentations, editorials and expert opinions.
• Exposure: Inherited (germline) pathogenic or likely pathogenic gene variants, and single nucleotide polymorphisms (SNPs), in relation to malignant mesothelioma risk, including possible asbestos–gene interaction. The review did not analyze specific asbestos fiber types.
• Main results:
  • 860 publications were retrieved from the databases and 4 more were found through reference lists. After exclusions, 81 articles were manually reviewed.
  • More than half of the genes reported in the literature to predispose to mesothelioma are involved in DNA repair, and most of these have a role in the homologous recombination pathway.
  • BAP1 mutation frequency reported in the reviewed literature: 0 to 7% for mesothelioma in distinct cases, rising up to 20% in familial cases. For comparison, the figures were 1 to 2% for uveal melanoma and 0.5% for cutaneous melanoma, rising to 25% and 0.7% respectively in familial cases.
  • Reviewed studies reported that malignant pleural mesothelioma patients with inherited mutations in DNA repair genes tend to have improved survival compared with those without a genetic alteration.
  • A figure reprinted from Hassan et al. (a different study) showed results for mesothelioma patients treated with platinum-based chemotherapy. Median survival was 8.0 years for all patients with inherited mutations versus 2.9 years for those without (p = 0.0006), and 7.9 versus 2.4 years for pleural mesothelioma (p = 0.0012). For peritoneal mesothelioma it was 8.2 versus 5.4 years (p = 0.47, not statistically significant).
  • Most reviewed studies described clinical features that can predict an inherited mutation: limited asbestos exposure, peritoneal disease, young age and a second cancer diagnosis.
  • Two genome-wide association studies were reviewed: one from Australia (428 mesothelioma patients and 778 controls) and one from Italy (407 patients and 389 controls). The Australian study tried but failed to replicate the most significant SNPs from the Italian study.
  • The authors noted no compelling evidence in the two genome-wide studies that the identified SNPs can cause mesothelioma in the absence of asbestos exposure.
  • In reviewed studies of carcinogen detoxification genes, a Finnish study (44 mesothelioma patients and 270 controls) and an Italian study (80 pleural mesothelioma patients and 255 healthy individuals) both linked the GSTM1 null genotype to pleural mesothelioma risk. The NAT2 slow acetylator was reported as increasing risk in the Finnish study but appeared protective in the Italian patients.
• The authors' conclusion: The authors concluded that only a few large studies exist on germline mutations and polymorphisms in mesothelioma. They wrote that genetic testing of high-risk individuals may facilitate genetic counseling and early cancer detection, and that identifying inherited mutations may help find candidates for targeted therapy.
• Limitations the authors state:
  • Only a few large studies have investigated germline mutations and polymorphisms in mesothelioma.
  • The prevalence and range of germline mutations in mesothelioma patients is not fully determined.
  • How these genetic alterations lead to mesothelioma is not yet fully determined.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Germline Mutation, Tumor Suppressor Gene, Hypoxia, Tumorigenesis.

Related studies

• 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)
• Melanoma genetics — J. Read, K.A. Wadt, et al. (2016)
• Hot spot mutations in Finnish non-small cell lung cancers — S. Mäki-Nevala, V.K. Sarhadi, et al. (2016)
• Germline BAP1 mutations predispose also to multiple basal cell carcinomas — A. de la Fouchardière, O. Cabaret, et al. (2015)
• Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma — M. Betti, E. Casalone, et al. (2017)
• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)

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