First Report of BAP1-Associated Polyposis

BAP1 Tumor Predisposition Syndrome (BAP1-TPDS) is caused by germline pathogenic variants in the BAP1 gene and has been associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and other benign cutaneous lesions. Adenomatous colon polyposis has not previously been reported as part of BAP1-TPDS. We report two patients with unexplained adenomatous oligopolyposis and germline BAP1 pathogenic variants. To determine if BAP1 had a role in polypogenesis, we performed somatic mutational analysis on multiple polyps from both patients (n = 8 total polyps tested). In every polyp tested, we found evidence of second BAP1 allele inactivation, including second somatic BAP1 mutations. Further, we did not detect any mutations in the commonly identified adenomatous polyposis pathway drivers, APC, CTNNB1, or other WNT/β-catenin. We did not detect somatic BAP1 mutations in any adenomatous polyps from patients without germline BAP1 pathogenic variants (n = 151 patients), highlighting the specificity of somatic BAP1 second hit mutations in BAP1 germline carrier polyps. Our findings strongly support that the polyps in these patients were caused by BAP1, and that adenomatous oligopolyposis is a part of the BAP1-TPDS tumor spectrum. Further work is needed to characterize the penetrance of this new BAP1-associated phenotype.