Genetic study of familial uveal melanoma: association of uveal and cutaneous melanoma with cutaneous and ocular nevi.

ABSTRACT

PURPOSE: To evaluate a kindred with familial uveal and cutaneous melanoma and to identify potential genetic and environmental factors that may predispose individuals to develop uveal melanoma. DESIGN: Family-based case report with detailed clinical and genetic evaluation. PARTICIPANTS: Ten siblings in a single nuclear family. METHODS: Evaluation of a large sibship via family history, complete eye and skin examinations, environmental risk factor questionnaire, and genetic testing, as well as a MEDLINE search of familial uveal melanoma kindreds. MAIN OUTCOME MEASURES: Cutaneous and ocular nevi, benign and malignant neoplasms of skin and other sites, brief skin cancer risk assessment tool risk classification for cutaneous melanoma, DNA sequencing of p16INK4a and p14ARF genes, and citations on familial uveal melanoma. RESULTS: The proband and his mother had uveal melanoma, 3 cutaneous melanomas occurred among 2 siblings, and 2 other siblings had basal cell carcinomas. No germline mutations were detected in the melanoma-associated tumor suppressor genes p16INK4a and p14ARF. Seven out of 10 siblings had a history of cutaneous and/or ocular nevi. Of the 3 subjects without nevi, 2 had histories of eye or skin malignancies (1 uveal melanoma, 1 basal cell carcinoma). Three of the 10 siblings had relevant ocular findings (2 choroidal nevi, 1 uveal melanoma). Six were also found to be in the "high-risk" classification for cutaneous malignancies based on scores from a previously validated risk assessment tool. This family, combined with the 91 previously reported familial uveal melanoma kindreds, brings to 92 the total number thus far recorded. CONCLUSIONS: Our results strengthen the association between uveal melanoma, atypical nevi, and cutaneous melanoma. This relationship supports the recommendation that individuals with a personal or family history of uveal melanoma, particularly in combination with atypical nevi, should be regularly screened for uveal and cutaneous melanoma.