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

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.

Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma

“…Although NF2 inactivation is clearly a driver of mesothelial carcinogenesis, it is possible that this inactivation does not play a role in tumor initiation for MPM, but will promote the development of a more aggressive tumor. This hypothesis is in line with several findings: (i) inactivation of NF2 in mouse models led to a variety of malignant tumors but not to mesothelioma [51], except if this inactivation was associated with asbestos exposure or with the inactivation of other tumor suppressor genes [52]; recent studies screening germline mutations in large cohorts of patients (reviewed in [44]) did not identify NF2 as a cancer susceptibility gene for MPM; and (iii) NF2 mutations showed a significantly higher mutation rate in MPM with an advanced stage [22]. We previously showed that MPM with mutations in members of the Hippo pathway could be more sensitive to specific anti-cancer molecules [53].…”

“…Germline mutations in cancer-related genes for 9 patients are reported in Additional file 1: Table S3A. Among genes previously reported as altered by pathogenic or likely pathogenic germline mutations in MPM [44], damaging variants were found in SDHA and PALB2 genes in patients T225LE and T277HP, respectively.…”

Employing hypoxia characterization to predict tumour immune microenvironment, treatment sensitivity and prognosis in hepatocellular carcinoma

“…Substantial data suggest that hypoxia is involved in promoting tumorigenesis [33] , progression [34] , and maintenance of malignant phenotype [35] . For example, the pressure of hypoxia provides an adaptation process of tumour cells reprogramming, contributing to proliferation, migration and invasion [36] , [37] , [38] .…”

Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial

“…Although several studies have expanded understanding of the genomic landscape of MPM and identified putative actionable alterations, these have not been translated to therapeutic progress [17][18][19] . More than 50% of MPMs carry germline or somatic mutations in genes involved in DNA repair and homologous recombination 3,20 . BAP1, a nuclear ubiquitin carboxyterminal hydrolase, has been reported to be frequently mutated in the germline and tumor cells of patients with MPM 17,18,20 .…”