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• W1982031059 abstract "To the Editor: Chromosomal region 9p21, which contains the CDKN2a and p14ARF tumor suppressor genes, has been found to be mutated or deleted in a variety of human cancers. CDKN2a encodes the p16INK4a protein that specifically blocks CDK4 and CDK6, thereby inhibiting the G1/S transition of the cell cycle. The p14ARF gene encodes a distinct protein that is derived in part from an alternative splicing of the CDKN2a gene and functions upstream of p53, interacting with the MDM2 oncoprotein. Alterations of these genes may result in uncontrolled cell growth and contribute to tumorigenesis. Several studies have shown the presence of CDKN2a mutations in a high proportion of familial melanomas, most of which segregate with the disease, suggesting that CDKN2a may represent the melanoma susceptibility gene (Soufir et al., 1998Soufir N. Avril M.-F. Chompret A. et al.Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France.Hum Mol Genet. 1998; 7: 209-216Crossref PubMed Scopus (348) Google Scholar). In contrast, the role of CDKN2a in the pathogenesis of sporadic melanoma is at present unclear. Whereas some authors (Wagner et al., 1998Wagner S.N. Wagner C. Briedigkeit L. Goss M. Homozygous deletion of the p16INK4a and the p15INK4b tumour suppressor genes in a subset of human sporadic cutaneous malignant melanoma.Br J Dermatol. 1998; 138: 13-21Crossref PubMed Scopus (46) Google Scholar) did not find any mutation or small deletion of CDKN2a in primary sporadic melanomas, other investigators detected a variable frequency of point mutations ranging from 7% to 33% (Healy et al., 1996Healy E. Sikkinik S. Rees J.L. Infrequent mutation of p16INK4a in sporadic melanoma.J Invest Dermatol. 1996; 107: 318-321Crossref PubMed Scopus (67) Google Scholar;Piccinin et al., 1997Piccinin S. Doglioni C. Maestro R. Vukosavljevic T. Gasparotto D. D’Orazi C. Boiocchi M. p16/CDKN2 and CDK4 gene mutations in sporadic melanoma development and progression.Int J Cancer (Pred Oncol). 1997; 74: 26-30Crossref PubMed Scopus (78) Google Scholar;Kumar et al., 1998Kumar R. Lundh Rozell B. Louhelainen J. Hemminki K. Mutations in the CDKN2a (p16INK4a) gene in microdissected sporadic primary melanomas.Int J Cancer. 1998; 75: 193-198Crossref PubMed Scopus (61) Google Scholar). Specific point mutations of the p14ARF gene have not yet been identified in familial or sporadic melanoma and therefore its role in this neoplasm is unknown. We analyzed the possible pathogenetic role of CDKN2a and p14ARF genes in 10 primary sporadic melanomas, which had been investigated previously for loss of heterozygosity (LOH) at 9p21 (locus D9S126) (Peris et al., 1995Peris K. Keller G. Chimenti S. Amantea A. Kerl H. Höfler H. Microsatellite instability and loss of heterozygosity in melanoma.J Invest Dermatol. 1995; 105: 625-628Crossref PubMed Scopus (67) Google Scholar). All samples had hemizygous deletions and represented different stages of melanoma progression. The Breslow thickness varied from 1.6 to 6 mm. In each case, exons 1α and 2 of the CDKN2a gene and the alternatively spliced exon 1β of the p14ARF gene were amplified using intronic oligonucleotide primers. For polymerase chain reaction (PCR) amplification, exon 2 was split into two overlapping fragments. PCR reactions were performed using standard conditions. Oligonucleotide sequences, PCR conditions, and length of amplified fragments are illustrated in Table 1. The PCR products were electrophoresed through 2% metaphore gel, then the specific bands were cut out and purified according to the manufacturer’s instructions (Qiagen, Hilden, Germany). Automated sequencing was performed with an ABI PRISM 310 Genetic Analyzer, Perkin-Elmer (Foster City, CA) Applied Biosystems. All the mutations were confirmed by sequencing both the forward and reverse strands; analyses were also repeated starting with independent PCRs.Table 1PCR primer sequences, amplification conditions, and length of the amplified fragmentsExonPrimer sequencesaF, forward; R, reverse.Temperature (°C)Length of amplified fragments (bp)1α5′-GAAGAAAGAGGAGGGGCTG-3′ (F) 5′-GCGCTACCTGATTCCAATTC-3′ (R)583401β5′-TCCCAGTCTGCAGTTAAGG-3′ (F) 5′-GTCTAAGTCGTTGTAACCCG-3′ (R)604122 (first part)5′-GGAAATTGGAAACTGGAAGC-3′ (F) 5′-GCAGCACCACCAGCGTG-3′ (R)602922 (second part)5′-GACCCGTGCACGACGCTG-3′ (F) 5′-TCTGAGCTTTGGAAGCTCT-3′ (R)55271a F, forward; R, reverse. Open table in a new tab In this study, one of 10 sporadic melanomas showed a C→T transition (C172T) at codon 58 of the CDKN2a gene. This mutation converts an arginine (CGA) to a stop codon (TGA) resulting in a truncated protein (Figure 1). Notably, as this case also showed LOH at 9p21 (D9S126), our results provide strong evidence for a bi-allelic inactivation of the CDKN2a gene in this tumor. Our findings are similar to those reported byHealy et al., 1996Healy E. Sikkinik S. Rees J.L. Infrequent mutation of p16INK4a in sporadic melanoma.J Invest Dermatol. 1996; 107: 318-321Crossref PubMed Scopus (67) Google Scholar who identified a CC→TT mutation at codons 57/58 of exon 2 in one of 14 melanomas with LOH at 9p21 (D9S162, D9S171). In addition, we detected a known polymorphic sequence variant (Ala148Thr) at exon 2 in three of 10 tumors. Finally, mutations of exon 1β of the p14ARF gene were not found in any sporadic melanoma examined, indicating that alterations of the p14ARF gene do not seem to play a crucial role in sporadic melanoma. Within chromosomal region 9p21, several tumor suppressor genes (e.g., CDKN2a, CDKN2b, and p14ARF) have been supposed to be implicated in the development of cutaneous melanoma. Among these, however, CDKN2a seems to represent by far the principal melanoma susceptibility gene mapping in this region. The earliest studies showed a high frequency (∼70%) of CDKN2a mutations or deletions in melanoma cell lines (Kamb et al., 1994Kamb A. Gruis N.A. Weaver-Feldhaus J. et al.A cell cycle regulator potentially involved in genesis of many tumor types.Sci. 1994; 264: 436-440Crossref PubMed Scopus (2814) Google Scholar;Pollock et al., 1995Pollock P.M. Yu F. Qiu L. Parsons P.G. Hayward N.K. Evidence for u.v. induction of CDKN2 mutations in melanoma cell lines.Oncogene. 1995; 11: 663-668PubMed Google Scholar). Although it has been assumed that a proportion of these alterations might have arisen as cell culture artefacts, analysis of mutation spectra reveals the prevalence of C:G→T:A transitions, C:G→A:T transversions, and CC→TT tandem mutations, the latter being unique to UV radiation. The possibility that CG→TG mutations of the CDKN2a gene, as detected in our study, may arise from spontaneously deaminated 5-methylcytosine seems unlikely in melanoma.Pollock et al., 1995Pollock P.M. Yu F. Qiu L. Parsons P.G. Hayward N.K. Evidence for u.v. induction of CDKN2 mutations in melanoma cell lines.Oncogene. 1995; 11: 663-668PubMed Google Scholar demonstrated that all C→T transitions at CG dinucleotides in melanoma cell lines occurred where the mutated cytosine was also the 3′ pyrimidine of a dipyrimidine pair, and that 20% of the CG→TG mutations found in CDKN2a in visceral malignant tumors occurred at cytosines preceded by a purine. More recently, point mutations of the CDKN2a gene have been also identified in primary sporadic melanoma.Gruis et al., 1995Gruis N.A. Weaver-Feldhaus J. Liu Q. et al.Genetic evidence in melanoma and bladder cancers that p16 and p53 function in separate pathways of tumor suppression.Am J Pathol. 1995; 146: 1199-1206PubMed Google Scholar found mutations in five of 34 (14.7%) melanomas, all of which are located in exon 2. A higher percentage (33%) of CDKN2a mutations has been detected byPiccinin et al., 1997Piccinin S. Doglioni C. Maestro R. Vukosavljevic T. Gasparotto D. D’Orazi C. Boiocchi M. p16/CDKN2 and CDK4 gene mutations in sporadic melanoma development and progression.Int J Cancer (Pred Oncol). 1997; 74: 26-30Crossref PubMed Scopus (78) Google Scholar in a series of 12 sporadic melanomas. Interestingly, two of four mutated cases showed a C→T base change at codons 70 and 75, respectively. Recently,Kumar et al., 1998Kumar R. Lundh Rozell B. Louhelainen J. Hemminki K. Mutations in the CDKN2a (p16INK4a) gene in microdissected sporadic primary melanomas.Int J Cancer. 1998; 75: 193-198Crossref PubMed Scopus (61) Google Scholar identified 11 CDKN2a mutations in eight of 31 (26%) sporadic melanomas with most mutations located in exon 1, and with two cases harboring multiple mutations. Notably, six of the 11 detected mutations were C→T transitions, four of which were at CC sites. The finding of C→T transitions in primary melanomas, as observed in our study and previous reports, is compatible with mutations arising in vivo as a result of exposure to ultraviolet radiation, as previously described at the p53 gene of nonmelanoma skin cancers. Therefore, taken together, an increasing body of evidence supports that UV radiation plays a direct role in the genesis of CDKN2a mutations and development of at least a subset of cutaneous melanomas. Whether CDKN2a alterations represent an early or late event in the pathogenesis of cutaneous melanoma remains unclear at present. Indeed, little is known about the role of CDKN2a in defined stages of melanoma progression and metastasis (Maelandsmo et al., 1996Maelandsmo G.M. FlØrenes V.A. Hovig E. et al.Involvement of the pRb/p16/cdk4/cyclin D1 pathway in the tumorigenesis of sporadic malignant melanomas.Br J Cancer. 1996; 73: 909-916Crossref PubMed Scopus (112) Google Scholar;Herbst et al., 1997Herbst R.A. Gutzmer R. Matiaske F. et al.Further evidence for ultraviolet light induction of CDKN2 (p16INK4) mutations in sporadic melanoma.In Vivo. J Invest Dermatol. 1997; 108: 950Abstract Full Text PDF PubMed Scopus (21) Google Scholar;Piccinin et al., 1997Piccinin S. Doglioni C. Maestro R. Vukosavljevic T. Gasparotto D. D’Orazi C. Boiocchi M. p16/CDKN2 and CDK4 gene mutations in sporadic melanoma development and progression.Int J Cancer (Pred Oncol). 1997; 74: 26-30Crossref PubMed Scopus (78) Google Scholar). Finally, because only a subset of primary sporadic melanomas harbors typical UV fingerprint mutations at the CDKN2a gene, we should consider that other mechanisms of CDKN2a inactivation, such as hypermethylation of the CpG island, or involvement of yet unidentified tumor suppressor genes at 9p21, might occur in the pathogenesis of sporadic melanoma." @default.
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• W1982031059 title "UV Fingerprint CDKN2a but No p14ARF Mutations in Sporadic Melanomas" @default.
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