Contribution of germline mutations in BRCA2, P16(INK4A), P14(ARF) and P15 to uveal melanoma.
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.
Hearle
Nicholas
N
Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom.
Damato
Bertil E
BE
Humphreys
Jane
J
Wixey
Julie
J
Green
Helen
H
Stone
Joanne
J
Easton
Douglas F
DF
Houlston
Richard S
RS
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*
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