Germline and Somatic Mutations in Human Mesothelioma and Lessons from Asbestos-Exposed Genetically Engineered Mouse Models

Like cancer generally, malignant mesothelioma is a genetic disease at the cellular level. Specific genes most frequently linked to mesothelioma include the tumor suppressor genes BAP1, CDKN2A, and NF2. Somatic (acquired) mutations of these and other tumor suppressor genes often occur in combination in a given mesothelioma, suggesting that a cascade of genomic alterations is involved in the pathogenesis of this deadly disease. Overall, only a small fraction of individuals exposed to asbestos fibers develop the disorder, suggesting that inherited genetic factors may play a role in predisposing to mesothelioma. A person who is genetically predisposed to mesothelioma carries a DNA variant in one or possibly more genes, but the disease may not be triggered unless there is exposure to asbestos—perhaps even minimally—or some other relevant carcinogenic environmental factor. For example, clustering of mesothelioma cases has been documented in some, but not all, families with a germline inactivating mutation of BAP1. People without a genetic predisposition also develop the disease when exposed to asbestos, but studies in humans and genetically engineered mouse models indicate that the risk is likely to be much lower. In this review, we highlight the current understanding of the role of both hereditary and somatic mutations in human malignant mesothelioma, as well as what has been learned from experimental studies of asbestos-exposed rodent models of mesothelioma.