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

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.

Keywords: BRCA1 associated protein 1 (BAP1); Malignant pleural mesothelioma (MPM); genetic counseling; genetic susceptibility; pleural tumors.

Figure 1

Relative contributions of different pathways to the onset of MPM. The different pathways whose disruption has been associated with MPM are represented as independent circles, which include the related genes. The thickness of the arrows is proportioned to the relative pathogenic contribution of each pathway (i.e., a larger arrow indicates a more substantive contribution). Promoting factors may lead to generic cancer syndromes (i.e., p53 and mTOR pathways) in addition to MPM or be specific to the latter (BAP1-TPDS1). MPM, malignant pleural mesothelioma.