Constitutional alterations in p16 in patients with uveal melanoma

Wang, X; Egan, Kathleen M.; Gragoudas, Evangelos S.; Kelsey, Karl T.

doi:10.1097/00008390-199612000-00001

Cited by 23 publications

(16 citation statements)

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“…We cannot rule out misdetection of mutations by SSCP, but this seems unlikely, as we recently reported one of the highest rates of p16 INK4A germline mutation in CMM families, using the same technical approaches (Soufir et al, 1998). Our data enhance results of two previous studies: Wang et al did not find any pathogenic mutation in 13 UMM patients with a family history of melanoma, either uveal (n = 6), or cutaneous (n = 7) (Wang et al, 1996); Singh et al did not detect either any mutation in eight families with two members affected with UMM (Singh et al 1996c). All 30 UMM families studied worldwide up to now have in common an absence of mutation in p16 INK4A , therefore supporting the rare involvement of this gene in genetic predisposition to UMM.…”

Section: Discussionsupporting

confidence: 70%

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

Soufir

Paillerets

Desjardins³

et al. 2000

Br J Cancer

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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.

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Section: Discussionsupporting

confidence: 70%

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

Soufir

Paillerets

Desjardins³

et al. 2000

Br J Cancer

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“…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.…”

Section: Discussionmentioning

confidence: 81%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Vajdic¹,

Kricker²,

Duffy³

et al. 2003

Melanoma Research

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Germline variants in the melanocortin 1 receptor gene (MC1R) and the p16 gene (CDKN2A) are associated with an increased risk of cutaneous melanoma. The frequency of these germline variants was examined in a populationbased, incident series of 62 ocular melanoma cases and ethnicity-matched population controls. In both cases and controls, 59% of individuals carried at least one MC1R variant and there were no significant differences in the frequency of any of the five most common variants of MC1R. We also found no significant differences between cases and controls in the frequency of any of the four most common variants of CDKN2A, and no melanoma case carried a deleterious germline CDKN2A mutation. Our findings argue against an important predisposing effect of the MC1R and CDKN2A genes for ocular melanoma.

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“…Wang et al 45 studied 13 patients with a family history of either uveal melanoma (n ϭ 7) or cutaneous melanomas (n ϭ 6). No pathogenic germline mutations in P16 INK4A were detected in any of the patients.…”

Section: Discussionmentioning

confidence: 99%

Contribution of Germline Mutations inBRCA2,P16^INK4A,P14^ARFandP15to Uveal Melanoma

Hearle

Damato

Humphreys

et al. 2003

Invest. Ophthalmol. Vis. Sci.

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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 P16 INK4Aand 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 , P14 ARF , and P15. RESULTS. One patient was found to harbor a Gly35Ala substitution in exon 1␣ 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, P16INK4A , P14 ARF , or P15. It is likely that mutations in other genes contribute to an inherited predisposition to uveal melanoma. (Invest Ophthalmol Vis Sci. 2003;44:458 -462)

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Constitutional alterations in p16 in patients with uveal melanoma

Cited by 23 publications

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

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

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

Contribution of Germline Mutations inBRCA2,P16^INK4A,P14^ARFandP15to Uveal Melanoma

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Constitutional alterations in p16 in patients with uveal melanoma

Cited by 23 publications

References 0 publications

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

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

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

Contribution of Germline Mutations inBRCA2,P16INK4A,P14ARFandP15to Uveal Melanoma

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Contribution of Germline Mutations inBRCA2,P16^INK4A,P14^ARFandP15to Uveal Melanoma