Individuals with presumably hereditary uveal melanoma do not harbour germline mutations in the coding regions of either the P16INK4A, P14ARF or cdk4 genes

Abstract

SummaryIn familial cutaneous malignant melanoma (CMM), disruption of the retinoblastoma (pRB) pathway frequently occurs through inactivating mutations in the p16 (p16 INK4A /CDKN2A/MTS1) gene or activating mutations in the G1-specific cyclin dependent kinase 4 gene (CDK4). Uveal malignant melanoma (UMM) also occurs in a familial setting, or sometimes in association with familial or sporadic CMM. Molecular studies of sporadic UMM have revealed somatic deletions covering the INK4A-ARF locus (encoding P16 INK4A and P14 ARF ) in a large proportion of tumours. We hypothesized that germline mutations in the p16 INK4A , p14 ARF or CDK4 genes might contribute to some cases of familial UMM, or to some cases of UMM associated with another melanoma. Out 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 identified 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 history of second melanoma, UMM (n = 1), or CMM (n = 1). We screened by polymerase chain reaction single-strand conformation polymorphism the entire coding sequence of the INK4A-ARF locus (exon 1α from p16 INK4A , exon 1β from p14 ARF , and exons 2 and 3, common to both genes), as well as the exons 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 predisposition to uveal melanoma.

Contribution of Germline Mutations inBRCA2,P16INK4A,P14ARFandP15to Uveal Melanoma

“…This is in keeping with observations by Singh et al, 7 but is lower than noted by Soufir et al, 42 who reported that 3.9% of patients had a family history of uveal melanoma. It is likely that these small differences reflect slight differences in ascertainment and the extent to which family histories were expanded.…”

Ocular melanoma is not associated with CDKN2A or MC1R variants — a population-based study

“…Deleterious germline mutations of CDKN2A have also not been found in previous studies of familial [11,12,14] and sporadic [8,13] ocular melanoma cases and ocular melanoma cases with a family history of cutaneous melanoma [11,14]. There is, however, some evidence that a loss of CDKN2A function may play a role in ocular melanoma.…”

“…The search for candidate susceptibility genes has focused on those known to be associated with cutaneous melanoma, e.g. the cell cycle regulatory genes, CDKN2A [7] and CDK4 [8], and the melanocortin 1 receptor gene (MC1R), a pigmentation-related gene [9,10], but no associations of germline mutations in these genes with ocular melanoma have been reported [8,[11][12][13][14][15].…”

Absence of BRAF gene mutations in uveal melanomas in contrast to cutaneous melanomas

“…Many other studies have found significant genetic (Naus et al, 2000;Soufir et al, 2000;Edmunds et al, 2002) and cytogenetic differences (Sisley et al, 2000) between the tumour types, despite both cells originating from the same cell type. Uveal melanoma is less studied in comparison to cutaneous melanoma, but to date no significant levels of mutated tumour-suppressor genes have so far been convincingly linked to it (Edmunds et al, 2002).…”