Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations.

INTRODUCTION: Inherited mutations are easily detected factors that influence the disease courses and optimal treatment strategies of some cancers. Germline mutations in BRCA1 associated protein 1 (BAP1) are associated with unique disease profiles in mesothelioma, atypical spitz nevi, and uveal melanoma, but the patient characteristics of an unselected population of BAP1 carriers identified by an ascertainment prevalence study are unknown.

METHODS: We collected blood samples, cancer histories, and occupational exposures from 183 unselected patients with BAP1-related diseases. Clinical information for each patient was obtained from medical records. Germline DNA was extracted from blood samples and sequenced using a next-generation sequencing assay. We tested screening criteria developed to identify patients with a possible germline BAP1 mutation.

RESULTS: Pathogenic or likely pathogenic germline BAP1 mutations were observed in 5 of 180 sequenced specimens and were exclusively found in patients identified by our screening criteria. Several patients with characteristics suspicious for a heritable deleterious mutation did not have a germline BAP1 mutation. The prevalence of pathogenic germline BAP1 mutations in patients with mesothelioma was 4.4% (95% confidence interval 1.1-11.1).

CONCLUSIONS: Results from the first unselected prevalence ascertainment study of germline BAP1 alterations suggest that the frequency of this mutation is low among patients with mesothelioma. The proposed screening criteria successfully identified all patients with germline BAP1-mutant mesothelioma. These screening guidelines may assist physicians in selecting patients who would benefit from genetic testing. Future efforts should validate and refine these criteria and search for other germline mutations associated with mesothelioma and related diseases.