Individuals with presumably hereditary uveal melanoma do not harbour germline mutations in the coding regions of either the P16(INK4A), P14(ARF) or cdk4 genes

In familial cutaneous malignant melanoma (CMM), disruption of the retinobla stoma (pRB) pathway frequently occurs through inactivating mutations in the p16 (p16(INK4A)/CDKN2A/MTS1) gene or activating mutations in the G1-specif ic cyclin dependent kinase 4 gene (CDK4). Uveal malignant melanoma (UMM) al so occurs in a familial setting, or sometimes in association with familial or sporadic CMM, Molecular studies of sporadic UMM have revealed somatic de letions covering the INK4A-ARF locus (encoding P16(INK4A) and P14(ARF)) in a large proportion of tumours. We hypothesized that germline mutations in t he p16(INK4A), p14(ARF) Or CDK4 genes might contribute to some cases of fam ilial UMM, or to some cases of UMM associated with another melanoma. Cut of 155 patients treated at the Institut Curie for UMM between 1994 and 1997, and interviewed about their personal and familial history of melanoma, we i dentified seven patients with a relative affected with UMM (n = 6) or CMM ( n = 1), and two patients who have had, in addition to UMM, a personal histo ry of second melanoma, UMM (n = 1), or CMM (n = 1). We screened by polymera se chain reaction single-strand conformation polymorphism the entire coding sequence of the INK4A-ARF locus (exon Ice from p16(INK4A), exon 1 beta fro m rho 14(ARF), and exons 2 and 3, common to both genes), as well as the exo ns 2, 5 and 8 of the CDK4 gene. coding for the functional domains involved in p16 and/or cyclin D1 binding. A previously reported polymorphism in exon 3 of the INK4A-ARF locus was found in one patient affected with bilateral UMM, but no germline mutations were detected, either in the p16(INK4A), p14 (ARF) Or CDK4 genes. Our data support the involvement of other genes in pre disposition to uveal melanoma. (C) 2000 Cancer Research Campaign.