ED13.06 Mesothelioma in a Setting of Germline BAP1 Mutations

Abstract

Individuals that are born with germline BAP1 mutations are affected by the BAP1 cancer syndrome. All individuals affected by this cancer syndrome have developed one or more malignancies in the course of their life. Mesothelioma, uveal and cutaneous melanomas –tumors often associated with exposure to environmental carcinogens-, are the most common malignancies, although almost any tumor type has been detected in carriers of this cancer syndrome. In addition, BAP1 mutant carriers develop multiple benign melanocytic tumors –histologically different from other SPITZ-like tumors- that we have called melanocytic BAP1 associated intradermal tumors (MBAITs) that can alert the physician that the patients is a carrier of the BAP1 cancer syndrome. Most malignancies develop after the 4th decade of life, although cancers in individuals as young as 19 years old have been detected. Because many of these malignancies, for example melanomas, can be cured by early detection, it is important to identify BAP1 mutant carriers that can be screened for early detection and curative resection. Moreover, carriers of germline BAP1 mutation may be at increased risk of developing mesothelioma and melanoma following exposure to low doses of asbestos, sunlight and X-Rays, thus cancer preventive measures can be implemented. When cancer develops in a setting of BAP1 germline mutations, these patients have a much better prognosis compared to patients with the same malignancies when they occur sporadically (i.e., not in carriers of BAP1 mutations). Familial mesotheliomas in these individuals occur in either the pleura or peritoneum (frequency ratio 1:1) at a median age of 56.3 years, have a male-to-female ratio of 0.73:1, and are associated with prolonged survival of 5 to 10 or more years, compared with a median age at diagnosis of 72, a pleural-to-peritoneal ratio of 86:14, a male-to-female ratio of 4:1, and a median survival of less than 1 year in sporadic mesothelioma. About 100 families with this mutated BAP1 cancer syndrome have been described in the United States, Europe, and New Zealand. Genetic studies demonstrated that these mutations are transmitted across multiple generations over the course of several centuries, and some US families carrying BAP1 mutations descend from a Swiss family that immigrated in the US in the early 1700s. An International Consensus Meeting sponsored by the IASLC supported medical screening for at-risk people who are carriers of BAP1 germline mutations as follows: (1) annual dermatological screening for early detection of melanoma at age 18 or younger; (2) annual eye examination/ophthalmoscopy for uveal melanoma at age 18 or younger; and (3) skin and eye examinations every 6 months after age of 30, when the frequency of cancer among carriers of germline BAP1 mutations starts to increase. It was also recommended that genetic counseling should be offered to all individuals tested for BAP1. Moreover, those with BAP1 germline mutations should be encouraged to participate in studies to improve early detection of mesothelioma (Carbone M. et al., Journal of Thoracic Oncology 11, 1246-1262, 2016). BAP1, mesothelioma, germline