(ChemotherapyAdvisor) – BAP1 causes familial uveal melanoma, a study presented at the 2012 American Society of Clinical Oncology Annual Meeting has found.

“Identification of BAP1 as the gene responsible for this syndrome is the first demonstration of a germline mutation causing uveal melanoma,” a very rare cancer type, noted Johan Hansson, MD, PhD, of the Karolinska Institute, Stockholm, Sweden. “This enables us to identify and monitor at-risk individuals belonging to mutation-positive families with predisposition to uveal melanoma, and possibly other cancer syndromes.”

He and his colleagues identified a family with hereditary predisposition for uveal melanoma. The proband is a young female who was diagnosed with uveal melanoma at the age of 16 years and developed liver metastases within six months. Two older paternal relatives diagnosed at age 39 and 44 years, respectively, were also identified.

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Massively parallel sequencing on germline DNA from the proband, her parents, and a healthy sibling was conducted. After mapping against the human reference genome, average coverage across the exome was between 35 and 86 for the four sequenced samples.

“Of the 260,000-plus single nucleotide variants and small insertion/deletion variants, 51 gene variants were filtered out by being novel, shared by the affected proband and her father (considered an obligate mutation carrier), but not by the healthy mother, of predicted functional importance and/or located within strongly conserved regions,” he reported.

Among these, the strongest candidate was a loss of function-variant in the BAP1 gene. BAP1 has been suggested as a tumor suppressor in several cancer-related syndromes, including uveal melanoma. Sequence data indicated an insertion of one base-pair in exon 3 of the BAP1 gene that caused a frame-shift and subsequently a truncated protein lacking its functional domains.

The mutation was also present in uveal melanoma tumor tissue from the two deceased paternal relatives and was found to segregate with the uveal melanoma phenotype in the family. “We also detected loss of heterozygosity in the tumor of the proband, supporting BAP1 as the causative gene in this family,” Dr. Hansson said.

Other cases of familial UM for mutations in BAP1 are being screened.