title: BAP1 germline mutation in two first grade family members with uveal melanoma.
abstract: BACKGROUND
  Uveal melanoma (UM) is the most common primary cancer of the eye in adults. About half of the patients are at risk of developing metastatic disease resulting in a poor clinical prognosis. Metastatic progression is strongly associated with loss of one chromosome 3 in the tumour (monosomy 3). The tumour suppressor gene BAP1 was found to be recurrently mutated in UM with monosomy 3. Familial UM is rare and amounts to about 0.6-6% of all patients with melanoma. However, BAP1 germline mutations have been identified in rare hereditary tumour syndromes, including cases with UM. One may assume that UM may be part of these hereditary conditions with predisposition to malignant cancers.
  
  
  METHODS
  The patients underwent complete ophthalmological workup and enucleation due to UM. Microsatellite analysis was performed to determine the chromosome 3 status of the tumours. Sanger sequencing of all coding exons of the BAP1 gene was performed in blood DNA of the patients.
  
  
  RESULTS
  Here we report on two family members (mother and son) diagnosed with UM. In both patients, a cosegregating BAP1 germline mutation (c.299 T>C) was found. The mutant BAP1 allele was retained in the tumour of the son showing monosomy 3. The son further developed urothelial carcinoma and liver metastasis, the mother was affected by the UM and cholangiocellular carcinoma.
  
  
  CONCLUSIONS
  [corrected] We detected a cosegregating BAP1 germline mutation in two family members with UM. This suggests that, consistent with a classic tumour suppressor model, carriers of damaging mutations in BAP1 are predisposed to UM. However, as BAP1 germline mutations have been found to cause other cancer syndromes as well, there must be other factors that decide about the type of tumour emerging from BAP1 inactivation.
authors.affiliation: Department of Ophthalmology, University of Regensburg, Germany.
authors.forename: David A
authors.initials: DA
authors.lastname: Maerker
authors.forename: Michael
authors.initials: M
authors.lastname: Zeschnigk
authors.forename: Jasmin
authors.initials: J
authors.lastname: Nelles
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Lohmann
authors.forename: Karl
authors.initials: K
authors.lastname: Worm
authors.forename: Anja K
authors.initials: AK
authors.lastname: Bosserhoff
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Krupar
authors.forename: Herbert
authors.initials: H
authors.lastname: Jägle
mesh_terms: D001706:Biopsy; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D005190:Family; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011379:Prognosis; D012189:Retrospective Studies; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism; D014604:Uveal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C400134:BAP1 protein, human; D004273:DNA, Neoplasm; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
keywords: Choroid; Ciliary body; Genetics; Neoplasia; Retina