A Founder Mutation In The Bap1 Gene Among Four Caucasian Families With High Incidences Of Malignant Peritoneal Mesothelioma And Uveal Melanoma: A Molecular And Genealogical Study In A 10-Generation Bap1 Cancer Syndrome Kindred

The BAP1 cancer syndrome is characterized by a high incidence of malignant mesothelioma (MM), uveal melanoma (UM), cutaneous melanoma (CM), clear cell renal cell carcinoma (ccRCC), and it is expected that the clinical phenotype will continue to broaden in scope. Molecular screening for BAP1 gene mutations among 29 patients selected for clinically apparent familial MM led to the identification of a heterozygous C base deletion mutation (c.1832delC, p.Leu573fs*3) shared by four of those patients. The frame shift deletion is predicted to truncate the BAP1 protein, and immunohistochemistry analysis of tumor specimens revealed predominant cytoplasmic staining. We genotyped 650K SNPs of the four MM samples and four controls and carried out principal component analysis and whole-genome identity-by-descent analysis using publicly available genotype data from the 1000 Genomes Project, UK10K Project, and NHIBL Exome Sequencing Project. These analyses showed that the four MM patients are of Central Europe ancestry and that some are related by a kinship coefficient of 0.0186. Haplotype analysis showed the presence of significantly shared segments around the BAP1 gene (LODu003e37.1). The pairwise extent of shared segments between any of the four MM patients ranged in length from 9.1 to 34.2 Mbp and indicates the c.1832delC variant originated in a recent common ancestor within five to ten generations. Through a combined molecular genomic and genealogical approach, we ascertained, to our knowledge, the largest known genealogically connected BAP1 cancer syndrome kindred (K4), whose members can trace descent from a common ancestor in the 17th century. This pedigree provided a unique opportunity to examine effects of BAP1 alteration on tumor expression on various body sites and would facilitate study of gene-gene and gene-environment interaction involving the BAP1 gene. It also suggests that molecular screening of the BAP1 gene, coupled with genealogical research, would be an effective strategy for the early detection and early intervention for BAP1-associated malignancies. Citation Format: Erin Flores, Mitsuru Emi, Todd Johnson, Tatsuhiko Tsunoda, Dusty Behner, Harriet Hoffman, Mary Hesdorffer, Masaki Nasu, Andrea Napolitano, Francine Baumann, Haining Yang, Michele Carbone. A founder mutation in the BAP1 gene among four caucasian families with high incidences of malignant peritoneal mesothelioma and uveal melanoma: a molecular and genealogical study in a 10-generation BAP1 cancer syndrome kindred. [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 4796. doi:10.1158/1538-7445.AM2015-4796