title: Contribution of germline mutations in BRCA2, P16(INK4A), P14(ARF) and P15 to uveal melanoma.
abstract: OBJECTIVE
  Reports suggest that a subset of uveal melanoma is familial. The association of uveal melanoma with breast and ovarian cancer and the increased risk in BRCA2-linked families implicates germline BRCA2 mutations as the cause of a subset of uveal melanomas. Similarly, the association between cutaneous and uveal melanomas in some families, coupled with the high frequency of somatic deletions of the INK4A-ARF locus in uveal melanomas, strongly suggests that mutations in P16(INK4A) and P15 account for a proportion of uveal melanomas.
  
  
  METHODS
  To examine this proposition, a systematically ascertained series of 385 patients with uveal melanoma were screened for germline mutations in BRCA2, P16(INK4A), P14(ARF), and P15.
  
  
  RESULTS
  One patient was found to harbor a Gly35Ala substitution in exon 1alpha of P16(INK4A), which has previously been reported to be pathogenic. No mutations were detected in P14(ARF) or P15. None of the patients harbored germline nucleotide changes that lead to truncation or that create or disrupt consensus splice sites of BRCA2 or missense variants with clear pathogenic potential.
  
  
  CONCLUSIONS
  These findings suggest that less than 2% of cases of uveal melanoma can be ascribed to germline mutations in BRCA2, P16(INK4A), P14(ARF), or P15. It is likely that mutations in other genes contribute to an inherited predisposition to uveal melanoma.
authors.affiliation: Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hearle
authors.forename: Bertil E
authors.initials: BE
authors.lastname: Damato
authors.forename: Jane
authors.initials: J
authors.lastname: Humphreys
authors.forename: Julie
authors.initials: J
authors.lastname: Wixey
authors.forename: Helen
authors.initials: H
authors.lastname: Green
authors.forename: Joanne
authors.initials: J
authors.lastname: Stone
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D024682:BRCA2 Protein / Q000235:genetics*; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D015994:Incidence; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*; D025521:Tumor Suppressor Proteins; D014604:Uveal Neoplasms / Q000235:genetics*
chemical_list: D024682:BRCA2 Protein; C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins