Genetic Predisposition to Mesothelioma: What Are the Biological Mechanisms and What Are the Clinical Characteristics of These Mesotheliomas?

Mesothelioma has been for many years the example of a malignancy induced exclusively by exposure to the environmental carcinogen asbestos. In recent years additional fibers, erionite and antigorite for example, and therapeutic ionizing radiation have been shown to cause mesothelioma. Most importantly, molecular genetic studies conducted by our team revealed that inactivating mutations of the BAP1 gene predispose individuals to mesothelioma. At times these mutations cause mesothelioma in combination with exposure to asbestos or to other carcinogens. Recent studies revealed that at least 12% of mesotheliomas develop in carriers of germline BAP1 mutations or, less frequently, of mutations of other tumor suppressor genes: these patients have a prolonged survival of 5 or more years. Thus mesothelioma has now become the preferred model to study gene x environment (GxE) interaction in human cancer. Genetic testing has become routine for mesothelioma patients in most major research hospitals and it is hoped that soon all patients will be tested to identify possible germline mutations as well tumor-specific mutations that can inform therapy. Moreover, family members of patients carrying BAP1 mutations can be tested, and if positive for mutations, they can be enrolled in early detection clinical trials that are often life-saving.