A BAP1 Mutation in a Danish Family Predisposes to Uveal Melanoma and Other Cancers

PLoS One. 2013 Aug 19;8(8):e72144. doi: 10.1371/journal.pone.0072144. eCollection 2013.

Abstract

Truncating germline mutations in the tumor suppressor gene BRCA-1 associated protein-1 (BAP1) have been reported in families predisposed to developing a wide range of different cancer types including uveal melanoma and cutaneous melanoma. There has also been an association between amelanotic tumor development and germline BAP1 mutation suggesting a possible phenotypic characteristic of BAP1 mutation carriers. Though there have been many types of cancer associated with germline BAP1 mutation, the full spectrum of disease association is yet to be ascertained. Here we describe a Danish family with predominantly uveal melanoma but also a range of other tumor types including lung, neuroendocrine, stomach, and breast cancer; as well as pigmented skin lesions. Whole-exome sequencing identified a BAP1 splice mutation located at c.581-2A>G, which leads to a premature truncation of BAP1 in an individual with uveal melanoma. This mutation was carried by several other family members with melanoma or various cancers. The finding expands on the growing profile of BAP1 as an important uveal and cutaneous melanoma tumor suppressor gene and implicates its involvement in the development of lung, and stomach cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amino Acid Sequence
  • Base Sequence
  • Case-Control Studies
  • DNA Mutational Analysis
  • Denmark
  • Female
  • Frameshift Mutation
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Loss of Heterozygosity
  • Male
  • Melanoma / enzymology
  • Melanoma / genetics*
  • Middle Aged
  • Molecular Sequence Data
  • Pedigree
  • Protein Isoforms / genetics
  • RNA Splice Sites
  • Tumor Suppressor Proteins / genetics*
  • Ubiquitin Thiolesterase / genetics*
  • Uveal Neoplasms / enzymology
  • Uveal Neoplasms / genetics*
  • Young Adult

Substances

  • BAP1 protein, human
  • Protein Isoforms
  • RNA Splice Sites
  • Tumor Suppressor Proteins
  • Ubiquitin Thiolesterase

Supplementary concepts

  • Uveal melanoma

Grant support

This work was supported by the Melanoma Research Alliance, the Swedish Cancer Society, the Swedish Research Council, the Berta Kamprad Foundation, the National Health and Medical Research Council (NHMRC) of Australia, and the Fight for Sight, Denmark. NKH and LGA receive salary support through a NHMRC Senior Principal Research Fellowship and ANZ Ph.D. scholarship, respectively. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.