Differential expression of p16INK4a and p16β transcripts in B-lymphoblastoid cells from members of hereditary melanoma families without CDKN2A exon mutations

Rizos, Helen; Becker, Therese M.; Holland, Elizabeth A.; Kefford, Richard; Mann, Graham J.

doi:10.1038/sj.onc.1201217

Cited by 23 publications

(15 citation statements)

References 29 publications

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“…The distribution of CDKN2A mutation types is consistent with that observed in the Human Genome Mutation Database. 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).…”

Section: Discussionmentioning

confidence: 86%

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

Goldstein¹,

Chan²,

Harland³

et al. 2006

Cancer Research

379

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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Section: Discussionmentioning

confidence: 86%

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

Goldstein¹,

Chan²,

Harland³

et al. 2006

Cancer Research

379

330

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“…p14ARF cDNA was synthesized using RT ± PCR and p14ARF speci®c primers from total RNA extracted from a lymphoblastoid cell line, as previously described (Rizos et al, 1997). ARF deletion and point mutants were engineered by PCR-mediated mutagenesis.…”

Section: Plasmid Constructsmentioning

confidence: 99%

Two arginine rich domains in the p14ARF tumour suppressor mediate nucleolar localization

et al. 2000

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The INK4a/ARF locus encodes two distinct tumour suppressors, p16 INK4a and p14ARF, that regulate cell cycle progression via the pRB and p53 pathways, respectively. The ARF protein inhibits hdm2 activity, leading to the stabilization of the p53 tumour suppressor and cell cycle inhibition. The amino-terminal domain of human p14ARF and of the mouse homologue, p19ARF, is su cient for these e ects. This domain is also su cient for the nucleolar localization of the mouse ARF protein. In contrast, we show that the human ARF protein requires two arginine rich domains, one in the amino-and the other in the carboxy-terminus, for nucleolar targeting. The amino-terminal nucleolar-targeting domain of p14ARF is also important for ARF-hdm2 binding and cell cycle inhibition. The carboxy-terminal p14ARF nucleolar localization domain lies within the shared INK4a/ARF exon 2, and is mutated in a small number of melanoma-prone kindreds. The INK4a/ARF exon2-mutations could a ect the function of both the p16 INK4a and p14ARF tumour suppressors. Oncogene (2000) 19, 2978 ± 2985.

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“…In two such families we found that the allele-speci®c expression of p14ARF from the chromosome segregating with disease was signi®cantly reduced (Rizos et al, 1997). If we also consider that 40% of melanoma-prone kindreds carry germline alterations that dually aect p16…”

Section: Ink4amentioning

confidence: 99%

A melanoma-associated germline mutation in exon 1β inactivates p14ARF

et al. 2001

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The INK4a/ARF locus encodes the cyclin dependent kinase inhibitor, p16INK4a and the p53 activator, p14ARF. These two proteins have an independent ®rst exon (exon 1a and exon 1b, respectively) but share exons 2 and 3 and are translated in dierent reading frames. Germline mutations in this locus are associated with melanoma susceptibility in 20 ± 40% of multiple case melanoma families. Although most of these mutations speci®cally inactivate p16 INK4a, more than 40% of the INK4a/ARF alterations located in exon 2, aect both p16INK4a and p14ARF. We now report a 16 base pair exon 1b germline insertion speci®cally altering p14ARF, but not p16 INK4a, in an individual with multiple primary melanomas. This mutant p14ARF, 60ins16, was restricted to the cytoplasm, did not stabilize p53 and was unable to arrest the growth of a p53 expressing melanoma cell line. This is the ®rst example of an exon 1b mutation that inactivates p14ARF, and thus implicates a role for this tumour suppressor in melanoma predisposition. Oncogene (2001) 20, 5543 ± 5547.

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Differential expression of p16INK4a and p16β transcripts in B-lymphoblastoid cells from members of hereditary melanoma families without CDKN2A exon mutations

Cited by 23 publications

References 29 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

Two arginine rich domains in the p14ARF tumour suppressor mediate nucleolar localization

A melanoma-associated germline mutation in exon 1β inactivates p14ARF

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