The genetic susceptibility in the development of malignant pleural mesothelioma

Our plain-English summary of The genetic susceptibility in the development of malignant pleural mesothelioma, by O. Melaiu, F. Gemignani, S. Landi (Journal of Thoracic Disease, 2018).

The study

• Authors: O. Melaiu, F. Gemignani, S. Landi
• Journal: Journal of Thoracic Disease
• Published: 2018;10(Suppl 2):S246-S252
• Type of article: Review
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a cancer of the pleural cavity whose main risk factor is exposure to asbestos. However, it has been shown that only a minority of exposed people develops MPM. In fact, the incidence among professionally exposed workers was shown to vary between 0.5% and 18.0%. Various hints suggested that other important cofactors could play a role, in particular the genetic susceptibility. Impressive is the case of Cappadocians families exposed to erionite and affected by an "epidemic" of MPM with about half of the inhabitants dying for the disease. However, no results for a "Cappadocia" gene of susceptibility to MPM have been obtained yet and more studies are needed. Among asbestos-exposed workers, several studies reported familial cases of MPM, suggesting that heredity could be important in the tumor development. However, large studies on familial clusters showed only weak increased risks that could be attributable also to indirect exposures in a contaminated household. Moreover, the risk of developing MPM is increased of a limited extent among people exposed to asbestos with a positive history of familial cancers. A particular is represented by carriers of germline mutations within BAP1 gene. In families and in animal models, mutations within BAP1 are strongly predisposing to develop MPM. However, also other types of cancer (such as uveal melanoma) are present, thus BAP1 mutations are considered as responsible for a hereditary form of a multi-cancer syndrome. In any case, among sporadic MPM, the prevalence of germline BAP1 mutations is negligible. Finally, genetic studies highlighted the presence of low-risk susceptibility alleles, such as those within XRCC3, NAT2 or GSTM1. Two different genome-wide association studies could not find positive associations reaching the genome-wide statistical significance threshold, however, both were concordant in showing a weak signal within the SDK1 gene region. Overall, it could be concluded that, as for other types of sporadic cancers, the susceptibility to develop MPM following asbestos exposure is modulated moderately by the individual genetic background. Further studies on larger series could help in a better characterization of more genes predisposing to MPM, being this tumor a rare disease.

In plain English

This is a review article, not a new study. The authors summarized published research on whether inherited genetic factors affect who develops malignant pleural mesothelioma (MPM) after asbestos exposure. They described reports of MPM in several members of one family, and noted that shared household asbestos exposure is a strong confounder for genetic explanations. They discussed Cappadocian villages in Turkey with very high MPM rates linked to erionite, a zeolite mineral, where no susceptibility gene had yet been found. They reviewed studies in which inherited BAP1 gene mutations strongly predisposed families and laboratory mice to mesothelioma, though such mutations were rare in people with sporadic MPM. Other reviewed studies linked MPM with common variants in genes such as GSTM1, NAT2 and XRCC3. In two genome-wide studies no variant reached genome-wide significance, though both pointed to the SDK1 gene region. The authors concluded that genetic susceptibility could play a mild role in sporadic MPM after asbestos exposure, while BAP1 mutations can greatly affect risk. They noted that because MPM is rare, adequately sized studies are difficult.

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 studies. The article does not describe how the studies were searched for or selected.
• Who was studied: Published studies covering several groups: family clusters of MPM; Cappadocian villages in Turkey and emigrants from them; families carrying BAP1 mutations and BAP1 mouse models; series of sporadic MPM cases; case-control studies of gene variants; and two genome-wide association studies. The two genome-wide studies were 428 MPM cases and 1,269 controls from Western Australia, and 407 MPM cases and 389 controls from Italy.
• Exposure: Asbestos exposure, both occupational and indirect (household), with fiber types mostly not specified. Erionite exposure in the Cappadocian villages. Crocidolite is mentioned in relation to BAP1 and the inflammatory response.
• Main results:
  • In a study by de Klerk et al. of 11,000 Wittenoom (Australia) asbestos workers, 369 families had at least one case of mesothelioma. There were a further 25 cases among relatives in those families, compared with 12.9 predicted cases.
  • Ohar et al. compared mesothelioma patients with other asbestos-exposed groups. Patients with mesothelioma had a greater risk of cancer among first-degree relatives (point estimate 2.93; 95% CI 2.50 to 3.50). The review authors judged the family-history evidence intriguing but not strong enough to confirm family history of cancer as a risk factor.
  • In Cappadocian families studied by Roushdy-Hammady and collaborators, 41 of 87 children with at least one parent affected by MPM developed MPM as adults.
  • In a study by Xu et al., BAP1 knockout mice chronically exposed to asbestos had a higher incidence of asbestos-induced mesothelioma than wild-type littermates (73% vs. 32%).
  • Studies of sporadic MPM found inherited BAP1 mutations to be rare. These included 103 sporadic cases studied by Betti et al., 78 cases with 1 germline variant studied by Rusch et al., and 115 cases with 0 germline variants studied by Sneddon et al.
  • In the two genome-wide association studies, no gene variant reached genome-wide statistical significance, likely because of limited numbers of patients. Both studies pointed to the SDK1 gene region.
• The authors' conclusion: The authors concluded that, following asbestos exposure, genetic susceptibility could play a mild role in the risk of sporadic MPM, similar to other human cancers. They concluded that inherited BAP1 mutations can greatly affect MPM risk as part of a multi-cancer syndrome, and that more studies are needed on genetics among Cappadocians.
• Limitations the authors state:
  • Because MPM is rare, it is difficult to carry out case-control studies large enough to have adequate statistical power.
  • Relatives of asbestos workers can be exposed indirectly at home, for example through contaminated work clothes. This is a strong confounder when studying genetic causes of family clusters.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Pleural Cavity, erionite, Cappadocia, Germline Mutation, BAP1, BAP1 Tumor Predisposition Syndrome, Statistical Significance.

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