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1From the Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom; the 2Liverpool Ocular Oncology Centre, Royal Liverpool University Hospital, Liverpool, United Kingdom; 3Cancer Research UK Genetic Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
PURPOSE. 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 P16INK4A 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, P16INK4A, P14ARF, and P15.
RESULTS. One patient was found to harbor a Gly35Ala substitution in exon 1
of P16INK4A, which has previously been reported to be pathogenic. No mutations were detected in P14ARF 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, P16INK4A, P14ARF, or P15. It is likely that mutations in other genes contribute to an inherited predisposition to uveal melanoma.
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