A mutation hotspot at the p14ARF splice site

Harland, Mark; Taylor, Claire; Chambers, P; Kukalizch, Kairen; Randerson-Moor, Juliette; Gruis, Nelleke A.; Snoo, Femke A. de; Huurne, Jeanet A.C. ter; Goldstein, Alisa M.; Tucker, Margaret A.; Bishop, D. Timothy; Newton-Bishop, Julia

doi:10.1038/sj.onc.1208678

Cited by 68 publications

(46 citation statements)

References 32 publications

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“…27 This finding is not surprising because the majority of disease-associated mutations identified to date are highly penetrant mutations associated with Mendelian disorders. In contrast, the seven ARF mutations were either novel splicing mutations (47) or large deletions (18,50); the five CDK4 mutations were all missense mutations that occurred in the same codon (7)(8)(9). Inheritance of the causal mutations of CDKN2A, ARF, and CDK4 are consistent with autosomal dominant inheritance with incomplete penetrance (41,51).…”

Section: Discussionmentioning

confidence: 88%

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

Goldstein¹,

Chan²,

Harland³

et al. 2006

Cancer Research

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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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Section: Discussionmentioning

confidence: 88%

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

Goldstein¹,

Chan²,

Harland³

et al. 2006

Cancer Research

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“…For p14 ARF , rare deletions and a 16-base-pair (bp) insertion at exon 1b with a mutational hot spot at the exon 1b splice site (Hewitt et al 2002;Harland et al 2005b) have also been reported. The presence of exon 1b-specific alterations suggest that p14ARF is a bona fide melanoma susceptibility gene independent from p16.…”

Section: High-risk Melanoma Locimentioning

confidence: 99%

Melanoma: from mutations to medicine

et al. 2012

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Melanoma is often considered one of the most aggressive and treatment-resistant human cancers. It is a disease that, due to the presence of melanin pigment, was accurately diagnosed earlier than most other malignancies and that has been subjected to countless therapeutic strategies. Aside from early surgical resection, no therapeutic modality has been found to afford a high likelihood of curative outcome. However, discoveries reported in recent years have revealed a near avalanche of breakthroughs in the melanoma field—breakthroughs that span fundamental understanding of the molecular basis of the disease all the way to new therapeutic strategies that produce unquestionable clinical benefit. These discoveries have been born from the successful fruits of numerous researchers working in many—sometimes-related, although also distinct—biomedical disciplines. Discoveries of frequent mutations involving BRAF(V600E), developmental and oncogenic roles for the microphthalmia-associated transcription factor (MITF) pathway, clinical efficacy of BRAF-targeted small molecules, and emerging mechanisms underlying resistance to targeted therapeutics represent just a sample of the findings that have created a striking inflection in the quest for clinically meaningful progress in the melanoma field.

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“…In practice, most of the CDKN2A germline mutations affect the sequence and function of p16 INK4A and have either a neutral or functionally imperceptible effect on p14 ARF . There are, nevertheless, examples of p14 ARF -specific mutations and deletions that are associated with genetic predisposition to melanoma [Rizos et al, 2001b;Laud et al, 2006;Harland et al, 2005]. P16 INK4A belongs to the INK4 family of CDK inhibitors that interact directly with the CDKs CDK4 and CDK6 and block their association with D-type cyclins.…”

Section: Introductionmentioning

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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A mutation hotspot at the p14ARF splice site

Cited by 68 publications

References 32 publications

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

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

Melanoma: from mutations to medicine

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

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