<i>CDKN2A</i> as a uveal and cutaneous melanoma susceptibility gene

Kannengiesser, Caroline; Avril, Marie-Françoise; Spatz, Alan; Laud, Karine; Lenoir, Gilbert; Paillerets, Brigitte Bressac-de

doi:10.1002/gcc.10286

Cited by 33 publications

(21 citation statements)

References 18 publications

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“…Some families with occurrence of both cutaneous and ocular melanomas have been described (see, for example, Kannengiesser et al, 2003). Subject IV-3 in our family presented with an ocular melanoma when he was 47 years old.…”

Section: A Sporadic Case Of Ocular Melanoma In the Familymentioning

confidence: 92%

A large Norwegian family with inherited malignant melanoma, multiple atypical nevi, and CDK4 mutation

Molven

Grimstvedt²,

Steine

et al. 2005

Genes Chromosomes & Cancer

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Mutations in two loci encoding cell-cycle-regulatory proteins have been shown to cause familial malignant melanoma. About 20% of melanoma-prone families bear a mutation in the CDKN2A locus, which encodes two unrelated proteins, p16INK4A and p14ARF. Mutations in the other locus, CDK4, are much rarer and have been linked to the disease in only three families worldwide. In the 1960s, a large Norwegian pedigree with multiple atypical nevi and malignant melanomas was identified. Subsequently, six generations and more than 100 family members were traced and 20 cases of melanoma verified. In this article, we report that CDK4 codon 24 is mutated from CGT to CAT (Arg24His) in this unusually large melanoma kindred. Intriguingly, one of the family members had ocular melanoma, but the CDK4 mutation could not be detected in archival tissue samples from this subject. Thus, the case of ocular melanoma in this family was sporadic, suggesting an etiology different from that of the skin tumors. The CDK4 mutation in the Norwegian family was identical to that in melanoma families in France, Australia, and England. Haplotype analysis using microsatellite markers flanking the CDK4 gene and single-nucleotide polymorphisms within the gene did not support the possibility that there was a common founder, but rather indicated at least two independent mutational events. All CDK4 melanoma families known to date have a substitution of amino acid 24. In addition to resulting from selection pressure, this observation may be explained by the CG dinucleotide of codon 24 representing a mutational hot spot in the CDK4 gene.

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Section: A Sporadic Case Of Ocular Melanoma In the Familymentioning

confidence: 92%

A large Norwegian family with inherited malignant melanoma, multiple atypical nevi, and CDK4 mutation

Molven

Grimstvedt²,

Steine

et al. 2005

Genes Chromosomes & Cancer

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“…Neural system tumors (NST) have also been reported to be associated with large deletions of CDKN2A/ARF and/or mutations that affect p14ARF but these studies are based on very small numbers of patients/families (17)(18)(19)(20)(21). Uveal melanoma (UM) occasionally also occurs in families with multiple CMM patients, suggesting the existence of possible common genetic factors, but to date, only one family with both UM and CMM and a CDKN2A germ-line mutation (p.G67S) has been reported (22).…”

Section: Introductionmentioning

confidence: 99%

High-risk Melanoma Susceptibility Genes and Pancreatic Cancer, Neural System Tumors, and Uveal Melanoma across GenoMEL

Goldstein¹,

Chan²,

Harland³

et al. 2006

Cancer Research

377

330

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GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of family's mutations) and the Netherlands (c.225_243del19, 90% of family's mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, c.IVS2-105A>G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available. (Cancer Res 2006; 66(20): 9818-28)

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“…Investigation of CDKN2A/P16 INK4A , P14 ARF and CDK4 genes CDKN2A (exons 1a, 2 and 3), ARF (exon 1b), and CDK4 (exon 2) point mutations were screened by direct sequencing by capillary electrophoresis performed on an ABI Prism 3730 Genetic Analyzer with Seqscape analysis software, version v2.0 (Applied Biosystems), as previously described [11]. CDK4 analysis has been restricted to exon 2 as no germline mutations were detected outside this exon, which contains two important P16 INK4A binding residues (Lys 22 and Arg 24) in full gene scanning [21,22].…”

Section: Nucleic Acid Extractionmentioning

confidence: 99%

“…The possible implication of CDKN2A in the genetic susceptibility to uveal melanoma has been demonstrated by identification of a deleterious germline mutation of this gene (exon 2; c.199G[A; p.G67S) in a melanoma-prone family comprising one case of uveal melanoma and two cases of malignant cutaneous melanoma (sister and daughter of the proband) [11]. A germline mutation of CDKN2A exon 1 was also identified in an individual diagnosed with apparently sporadic uveal melanoma at the age of 59 years [15].…”

mentioning

confidence: 99%

“…Several biological and clinical observations suggest that inherited susceptibility to uveal melanoma may be partly mediated by genes conferring an increased risk of cutaneous melanoma, namely the CDKN2A/P16 INK4A gene for which monoallelic alterations are responsible for 20-40% of familial forms of cutaneous melanoma: uveal and cutaneous melanocytes have a common neural crest origin; somatic deletions of the CDKN2A/ARF locus and reduced expression of P16INK4A via promoter hypermethylation have been reported in a significant proportion of human uveal melanomas and uveal melanoma cell lines [7][8][9]; finally, an association of uveal and cutaneous melanomas in some individuals or in two or more relatives has been reported [10][11][12][13][14]. The possible implication of CDKN2A in the genetic susceptibility to uveal melanoma has been demonstrated by identification of a deleterious germline mutation of this gene (exon 2; c.199G[A; p.G67S) in a melanoma-prone family comprising one case of uveal melanoma and two cases of malignant cutaneous melanoma (sister and daughter of the proband) [11].…”

mentioning

confidence: 99%

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Contribution of CDKN2A/P16 INK4A, P14 ARF, CDK4 and BRCA1/2 germline mutations in individuals with suspected genetic predisposition to uveal melanoma

et al. 2010

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Uveal melanoma arises from melanocytes of the uveal tract (iris, ciliary body and choroid) and represents the most common intraocular malignancy in adults. Some rare clinical situations (young age at diagnosis, bilateral or multifocal forms, association with cutaneous malignant melanoma and/or familial aggregations of melanomas) are suggestive of genetic susceptibility. The aim of this study was to evaluate the contribution of CDKN2A/P16INK4A, P14ARF and CDK4 gene germline mutations in a series of patients with uveal melanoma recruited in a single institution with a clinical presentation indicative of genetic predisposition. Molecular analyses were proposed to 36 patients and were performed in 25 cases. The contribution of BRCA1/2 gene germline mutations in patients with uveal melanoma and a personal and/or family history of breast/ovarian cancers was also evaluated. Molecular analysis of BRCA1/2 genes was proposed to 35 patients and was performed in 25 patients. No deleterious germline mutation was identified in either group of patients. These results indicate that the CDKN2A/P16INK4A, P14ARF, CDK4 genes are not responsible for the vast majority of genetic susceptibility to uveal melanoma. They also suggest that one case of uveal melanoma in a family with a history of breast cancer is not sufficient to justify BRCA1/2 genetic testing when the classical criteria for molecular analysis are not present. International studies are ongoing in melanoma-prone families in an attempt to identify uveal melanoma susceptibility loci and genes.

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CDKN2A as a uveal and cutaneous melanoma susceptibility gene

Cited by 33 publications

References 18 publications

A large Norwegian family with inherited malignant melanoma, multiple atypical nevi, and CDK4 mutation

A large Norwegian family with inherited malignant melanoma, multiple atypical nevi, and CDK4 mutation

High-risk Melanoma Susceptibility Genes and Pancreatic Cancer, Neural System Tumors, and Uveal Melanoma across GenoMEL

Contribution of CDKN2A/P16 INK4A, P14 ARF, CDK4 and BRCA1/2 germline mutations in individuals with suspected genetic predisposition to uveal melanoma

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