Abstract Background: Malignant mesothelioma (MM) is a lethal tumor whose pathogenesis results from complex interactions between host genetics and environmental carcinogens. BAP1 mutations were reported in 22% and 23% of sporadic MM in two US Caucasian studies whereas BAP1 mutations were found in 61% of sporadic MM in a Japanese study. The significant discrepancy in frequency of BAP1 mutations suggested either a possible influence of ethnicity or differences related to the methodological approaches. Methods: To investigate this apparent discrepancy, we carried out comprehensive genomic analyses using multiple techniques in order to detect somatic alterations of the BAP1 gene in tumors of 22 US Caucasian MM patients. Results: Six mutations were detected by Sanger sequencing, gross gene alterations were found in 7 MM specimens by Multiplex Ligation-Dependent Probe Amplification and copy number analysis, and a new splice variant was identified by cDNA sequencing. Changes in methylation were not observed in our study. Immunohistochemistry (IHC) revealed nuclear BAP1 staining in the 8 MM tumors containing wild-type BAP1 while tumor cells in the 14 biopsies with mutated BAP1 did not show any nuclear staining. We extended our BAP1 IHC analysis to an independent cohort of MM samples from the National Virtual Mesothelioma Bank and we found loss of BAP1 nuclear staining in 46 out of 67 biopsies. Moreover we found similar frequency of BAP1 loss across different MM histological subtypes. Conclusions: We identified somatic alterations of the BAP1 gene in 73.7% of Caucasian MM tumors in two independent cohorts of somatic MMs, underscoring the need to apply integrated genomic analyses to scrutinize the BAP1 gene for its alterations. Immunohistochemistry was the most reliable technique to detect BAP1 mutations in MM biopsies. The high incidence of alterations establishes BAP1 as the most commonly mutated gene in MM, regardless of ethnic background or histological subtype. Citation Format: Masaki Nasu, Sandra Pastorino, Hugh Luk, Erin Flores, Francine Baumann, Amy Powers, Shreya Kanodia, Giovanni Gaudino, Yu-an Zhang, Adi Gazdar, Haining Yang, Harvey I. Pass, Mitsuru Emi, Michele Carbone. High incidence of somatic BAP1 alterations in sporadic malignant mesothelioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3944. doi:10.1158/1538-7445.AM2015-3944