Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma

Soufir, Nadem; Lacapère, J; Bertrand, Guylène; Matichard, E.; Meziani, Roubila; Mirebeau, Delphine; Descamps, V.; Gérard, Bénédicte; Archimbaud, Alain; Ollivaud, L.; Bouscarat, F.; Baccard, M.; Lanternier, Guy; Saïag, Philippe; Lebbe, Célèste; Basset-Séguin, Nicole; Crickx, B; Cavé, Hélène; Grandchamp, Bernard

doi:10.1038/sj.bjc.6601503

Cited by 35 publications

(35 citation statements)

References 61 publications

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“…Our findings were confirmed by a very recent investigation that was reported after our study was performed [27]. These investigators analysed germline mutations in CDKN2A and exon 2 of CDK4 in 21 patients with CM diagnosed before the age of 25 years, and found a single CDKN2A exon 2 mutation.…”

Section: Discussionsupporting

confidence: 95%

Germline CDKN2A mutations are rare in child and adolescent cutaneous melanoma

Berg¹,

Wennberg

Tuominen

et al. 2004

Melanoma Research

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Early-onset melanoma under the age of 20 years is still a rare disease but has an increasing incidence. The aim of this study was to determine whether CDKN2A germline mutations are present in patients diagnosed with childhood/adolescent melanoma. From the Swedish Cancer Register we identified 60 patients with a diagnosis of cutaneous malignant melanoma before the age of 20 years. A medical history including information on self-reported melanoma heredity was obtained, a physical examination was performed by a dermatologist, and the histopathology slides were reviewed. A blood test was obtained for analysis of germline CDKN2A exon 1 and exon 2 mutations by DNA sequencing. We found only one germline CDKN2A mutation with functional significance, which was an exon 1 missense mutation resulting in a proline-to-leucine substitution in codon 48. This mutation was seen in a patient belonging to a previously reported kindred with hereditary melanoma where this particular germline CDKN2A mutation had been identified. Thus, in the large majority of cutaneous melanoma in childhood/adolescence, any underlying genetic alterations have yet to be identified.

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Section: Discussionsupporting

confidence: 95%

Germline CDKN2A mutations are rare in child and adolescent cutaneous melanoma

Berg¹,

Wennberg

Tuominen

et al. 2004

Melanoma Research

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“…Three patients (0.8%) positive for a CDK4 Arg24His mutation were identified, and they were all later confirmed to belong to the large Norwegian family reported by Molven et al (2005). Alterations in the CDK4 gene represent a rare cause of familial malignant melanoma (Eliason et al, 2006;Soufir et al, 2004). Notably, other gene variants were not observed in the screened part of CDK4, eliminating the possibility of other mutations within or close to exon 2 representing a significant risk factor in MPM patients.…”

Section: Discussionmentioning

confidence: 77%

Population‐based prevalence of CDKN2A and CDK4 mutations in patients with multiple primary melanomas

Helsing

Nymoen

Ariansen

et al. 2007

Genes Chromosomes & Cancer

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The presence of multiple primary cutaneous melanomas (MPM) has been advocated as guidance to identifying melanoma families. Frequencies of CDKN2A mutations in materials of sporadic MPM cases from pigmented lesion clinics vary between 8 and 15%. Patients with MPM have therefore been regarded as good candidates for CDKN2A mutational screening. We describe a population-based study where all persons in Norway diagnosed with MPM between 1953 and 2004 (n = 738 alive per April 2004) were invited to participate. Three-hundred-and-ninety patients (52.8%) responded confidentially. Mutations in CDKN2A were found in 6.9% of the respondents. Eighty-one MPM patients (20.8%) reported that they belonged to melanoma families, and 17 (21.0%) of these harboured a CDKN2A mutation, compared to 3.2% of the nonfamilial cases. The probability of finding a CDKN2A mutation increased when the patients had three or more melanomas, or a young age of onset of first melanoma. We identified five novel CDKN2A variants (Ala57Gly, Pro81Arg, Ala118Val, Leu130Val, and Arg131Pro) and four that previously have been reported in melanoma families (Glu27X, Met53Ile, Arg87Trp, and Ala127Pro). A large deletion (g.13623_23772del10150) encompassing exon 1alpha and the 5' part of exon 2 was detected in six patients with a family history of melanoma. Three patients, belonging to the same family, had the CDK4 Arg24His mutation. The frequency of CDKN2A mutations was lower than previously reported in other studies, an observation which probably is due to the population-based design of our study.

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“…However, we observed that all mutations with clear loss of function were detected either in MPM or FM, in accordance with the proposed hypothesis that CDKN2A mutations displaying loss of function demonstrate a substantial increased risk of melanoma. The two variants without evident loss of function, Arg24Gln and Ala57Val, were not detected to date in melanoma-prone families but in MPM patients and a single primary melanoma (SPM) also affected by a pancreatic cancer [Soufir et al, 2004]. None of these two variants were detected in a population of 202 Caucasian controls, in SNP databases, or in the largest world-wide population-based study of 2,424 SPM [Orlow et al, 2007].…”

Section: Ink4amentioning

confidence: 99%

“…To date, it has been detected in three MPM cases (Patient 1468) [Orlow et al, 2007], a false FM (affected Proband 19696 whose melanoma-affected sister is not carrier) and a patient affected by malignant melanoma (MM) and pancreatic cancer [Soufir et al, 2004]. In addition, it has been described as a somatic alteration in various types of cancers, including leukemia, and lung and pancreatic carcinoma [Quesnel et al, 1995;Gazzeri et al, 1998; Gretarsdottir et al, 1998].…”

Section: Ink4amentioning

confidence: 99%

Functional, structural, and genetic evaluation of 20CDKN2Agerm line mutations identified in melanoma-prone families or patients

Kannengiesser¹,

Brookes²,

Arroyo³

et al. 2009

Hum. Mutat.

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Germline mutations of the CDKN2A gene are found in melanoma-prone families and individuals with multiple sporadic melanomas. The encoded protein, p16INK4A , comprises four ankyrin-type repeats, and the mutations, most of which are missense and occur throughout the entire coding region, can disrupt the conformation of these structural motifs as well as the association of p16INK4a with its physiological targets, the cyclin-dependent kinases (CDKs) CDK4 and CDK6. Assessing pathogenicity of nonsynonymous mutations is critical to evaluate melanoma risk in carriers. In the current study, we investigate 20 CDKN2A germline mutations whose effects on p16 INK4A structure and function have not been previously documented (Thr18_Ala19dup, Gly23Asp, Arg24Gln, Gly35Ala, Gly35Val, Ala57Val, Ala60Val, Ala60Arg, Leu65dup, Gly67Arg, Gly67_Asn71del, Glu69Gly, Asp74Tyr, Thr77Pro, Arg80Pro, Pro81Thr, Arg87Trp, Leu97Arg, Arg99Pro, and [Leu113Leu;Pro114Ser]). By considering genetic information, the predicted impact of each variant on the protein structure, its ability to interact with CDK4 and impede cell proliferation in experimental settings, we conclude that 18 of the 20 CDKN2A variants can be classed as loss of function mutations, whereas the results for two remain ambiguous. Discriminating between mutant and neutral variants of p16INK4A not only adds to our understanding of the functionally critical residues in the protein but provides information that can be used for melanoma risk prediction.

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Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma

Cited by 35 publications

References 61 publications

Germline CDKN2A mutations are rare in child and adolescent cutaneous melanoma

Germline CDKN2A mutations are rare in child and adolescent cutaneous melanoma

Population‐based prevalence of CDKN2A and CDK4 mutations in patients with multiple primary melanomas

Functional, structural, and genetic evaluation of 20CDKN2Agerm line mutations identified in melanoma-prone families or patients

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