The existence of families with multiple members having malignant mesothelioma has been known for some time and suggests the existence of germline variants that confer an increased risk, even in the absence of exposure to asbestos. However, the prevalence of variant forms of known cancer susceptibility genes in patients with mesothelioma is largely unknown. Now, data from a next-generation sequencing analysis provide evidence for the genetic basis of familial mesothelioma risk.
DNA samples from a cohort of 198 unrelated patients with mesothelioma of the pleura (75%), peritoneum (22%), pleura and peritoneum (2%), and tunica vaginalis (2%) were analysed for germline mutations in 85 established cancer susceptibility genes. At least one germline mutation was detected in 12% of patients, of which a quarter had mutations in ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1), an enzyme involved in BRCA1 signalling. The majority of other variants were also in genes involved in DNA repair and/or regulation of the cell cycle.
Germline mutations were significantly less likely to be detected in patients with tumours in a pleural location and in those with previous asbestos exposure, but were more likely to be detected in those with a second diagnosis of cancer.
Mutations in BAP1 have been previously identified in patients with an increased familial risk of mesothelioma, although this was not a consistent observation. These findings demonstrate that mutations in genes that encode other DNA repair and/or cell cycle proteins, or even those that encode proteins with other functions, might also be associated with mesothelioma, thus explaining this apparent dichotomy.
Investigators note that the prevalence of germline alterations observed in this study is similar to that of patients with other solid tumours. Investigations designed to target vulnerabilities created by these alterations, including selective use of poly(ADP-ribose) polymerase (PARP) inhibitors, are currently underway.
Panou, V. et al. Frequency of germline mutations in cancer susceptibility genes in malignant mesothelioma. J. Clin. Oncol. https://doi.org/10.1200/JCO.2018.78.5204 (2018)
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Sidaway, P. Mesothelioma risk genes revealed. Nat Rev Clin Oncol 15, 655 (2018). https://doi.org/10.1038/s41571-018-0092-1