Germline p16 mutations in familial melanoma

Hussussian, Christopher J.; Struewing, Jeffery P.; Goldstein, Alisa M.; Higgins, Paul A. T.; Ally, Delphine S.; Sheahan, Michelle D.; Clark, Wallace H.; Tucker, Margaret A.; Dracopoli, Nicholas C.

doi:10.1038/ng0994-15

Cited by 1,114 publications

(692 citation statements)

References 17 publications

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“…In a subset of these kindreds, germline coding mutations of the CDKN2A gene (on human chromosome 9p21) co-segregate with cases of melanoma (Hussussian et al, 1994;Walker et al, 1995;Dracopoli and Fountain, 1996;FitzGerald et al, 1996; NL and DH, unpublished). The CDKN2A gene product ± designated p16 ± is a cyclin-dependent kinase (CDK) inhibitor (CDKI).…”

Section: Abstract: Familial Melanoma; Cdk6mentioning

confidence: 99%

Lack of germline CDK6 mutations in familial melanoma

et al. 2000

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Germline mutations in genes encoding several components of the retinoblastoma pathway have been linked with inherited predisposition to melanoma. Most commonly, such mutations involve CDKN2A, a cyclindependant kinase inhibitor of two kinases, CDK4 and CDK6, which phosphorylate the retinoblastoma protein (pRB) and thereby promote passage through the G 1 /S cell-cycle restriction point. Less frequently, germline mutations in the CDK4 gene have also been linked with an increased risk of melanoma. Despite the sequence and functional homology between CDK4 and CDK6, the role of germline mutations in CDK6 in melanoma predisposition is unknown. We detected no CDK6 mutations within the p16 (CDKN2A) binding domain in index cases from 60 melanoma-prone kindreds that lacked germline mutations in the coding regions of either CDKN2A or within the entire CDK4 coding region. We conclude that germline mutations in CDK6 do not make a signi®cant contribution to melanoma predisposition. Oncogene (2000) 19, 1849 ± 1852. Keywords: familial melanoma; CDK6Between 8 and 12% of melanoma cases arise in families with a genetic predisposition to the disease (Tucker and Goldstein, 1995). In a subset of these kindreds, germline coding mutations of the CDKN2A gene (on human chromosome 9p21) co-segregate with cases of melanoma (Hussussian et al., 1994;Walker et al., 1995;Dracopoli and Fountain, 1996;FitzGerald et al., 1996; NL and DH, unpublished). The CDKN2A gene product ± designated p16 ± is a cyclin-dependent kinase (CDK) inhibitor (CDKI). p16 plays a key regulatory role in the retinoblastoma (Rb) pathway at the G 1 /S cell-cycle restriction point by inhibiting the phosphorylation of Rb via CDK4/6 (Kato et al., 1993;Weinberg, 1995;Ruas and Peters, 1998). The genetic basis for melanoma in families and individuals that lack coding mutations of CDKN2A is not well understood at this time. Possible explanations include non-coding mutations of CDKN2A; alterations in other genes located at 9p21; and mutations of other major or minor melanoma predisposition genes located elsewhere in the human genome.Genetic alterations of two other members of the Rb pathway in addition to CDKN2A have been linked with an increased risk of melanoma. Individuals harbouring germline mutations in the Rb gene and who have retinoblastoma as children show an increased risk of melanoma as adults (Draper et al., 1986;Traboulsi et al., 1988;Eng et al., 1993;Bataille et al., 1995). In addition, three melanoma prone families have been reported to possess germline mutations in the CDK4 gene that cosegregate with the disease. Two of these families possess a cysteine rather than the wild-type arginine at amino acid 24 (R24C; Zuo et al., 1996). More recently, an additional mutation at position 24 (R24H) was identi®ed in a single French kindred (Sou®r et al., 1998). Moreover, the R24C (and presumably the R24H) mutant protein has a reduced a nity for p16, resulting in relaxation of control at the G1/S restriction point. CDK6 shows considerable amino acid homology with CDK4 ( Figure...

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Section: Abstract: Familial Melanoma; Cdk6mentioning

confidence: 99%

Lack of germline CDK6 mutations in familial melanoma

et al. 2000

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“…When pRb is phosphorylated in these complexes the E2F proteins are free to transactivate their target genes and their products promote cell cycle progression (Sherr, 1996). Mutation of INK4a was ®rst demonstrated in familiar melanoma (Hussussian et al, 1994;Kamb et al, 1994) and INK4a remains the only member of the INK4 family shown to act as a tumor suppressor gene in humans. Mutation, deletion, or methylation of INK4a is common in many tumors, with a frequency ranging from approximately 30% in esophageal tumors, to nearly 100% in pancreatic carcinomas (Caldas et al, 1994;Ruas and Peters, 1998;Schutte et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Tissue-specific alternative splicing in the human INK4a/ARF cell cycle regulatory locus

Robertson

Jones

1999

Oncogene

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The INK4a/ARF locus on human chromosome 9p resides at the nexus of two critical cell cycle regulatory pathways, the p53 pathway and the retinoblastoma (pRb) gene pathway. Through the use of shared coding regions and alternative reading frames two distinct proteins are produced: INK4a is a cyclin-dependent kinase inhibitor whereas ARF binds the MDM2 protooncogene and stabilizes p53. We have examined the expression patterns of the INK4a/ARF locus at the RNA level in normal human and murine tissues to determine if these genes are coordinately regulated. We found that both INK4a and ARF were expressed in most tissues at low levels detectable only by RT ± PCR. The pancreas was an exception in that it expressed no detectable ARF mRNA but expressed high levels of INK4a mRNA. Furthermore, human pancreas expressed an additional previously unrecognized splice variant of INK4a, termed p12, through the use of an alternative splice donor site within intron 1. The p12 transcript produced a 12 kD protein composed of INK4a exon 1a and a novel intronderived C-terminus. This novel protein did not interact with cdk4 but was capable of suppressing growth in a pRb-independent manner. The implications of the capacity of the INK4a/ARF locus to encode a third transcript, and for pancreatic cancer, in which the INK4a/ARF locus is nearly always altered, are considered.

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“…Loss of such an inhibitor would probably result in unregulated proliferation, thus reinforcing the support for p16 as a tumour suppressor. More recently, the availability of thepl6-/-mouse (Serrano et al, 1996) and the observation that some familial melanoma families harbour germnlne point mutations or deletions within the p16 gene (Hussussian et al, 1994;Gruis et al, 1995) have provided further evidence that p16 is a tumoursuppressor gene. A second gene in this region, p15, also behaves as a tumour suppressor (Sonada et al, 1995).…”

mentioning

confidence: 99%

Loss of heterozygosity at chromosome 9p in ductal carcinoma in situ and invasive carcinoma of the breast

Marsh

Varley²

1998

Br J Cancer

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Summary Twenty-three cases of ductal carcinoma in situ (DCIS), ten of which had an associated invasive component, were studied for loss of heterozygosity (LOH) of microsatellite markers on chromosome 9p and the results compared with a panel of 20 invasive breast carcinomas. In addition to the gene encoding p16, chromosome 9p is also thought to contain other putative tumour-suppressor genes. If the three panels of breast tumours showed LOH of markers in this region this would suggest that such putative genes were important in breast carcinogenesis. By studying both preinvasive and invasive breast tumours, it should also be possible to gain further information about the relationship between lesions of a different stage and to determine whether DCIS is indeed a precursor of invasive ductal carcinoma. Levels of LOH were low in the invasive-only set of tumours. Surprisingly, considerably higher levels of loss were observed in the tumours with an in situ component. Also, much heterogeneity was observed between different DCIS ducts or invasive tumour and DCIS from the same case.

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Germline p16 mutations in familial melanoma

Cited by 1,114 publications

References 17 publications

Lack of germline CDK6 mutations in familial melanoma

Lack of germline CDK6 mutations in familial melanoma

Tissue-specific alternative splicing in the human INK4a/ARF cell cycle regulatory locus

Loss of heterozygosity at chromosome 9p in ductal carcinoma in situ and invasive carcinoma of the breast

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