CDKN2A: the IVS2-105A/G intronic mutation found in an Italian patient affected by eight primary melanomas

Journal of Investigative Dermatology (Impact Factor: 7.22). 03/2004; 122(2):450-1. DOI: 10.1046/j.0022-202X.2004.22222.x
Source: PubMed


The Journal of Investigative Dermatology publishes basic and clinical research in cutaneous biology and skin disease.

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    • "In the CDKN2A promoter region germline mutations occur rarely (Liu et al. 1999; Harland et al. 2000; Pollock et al. 2001). Recently, the lack of detectable mutations has been partly explained by the observation of noncoding mutations deep in the introns (Harland et al. 2001; Majore et al. 2004; Harland et al. 2005a). However, there are still a signifi cant proportion of 9p21-linked families in which the susceptibility to melanoma remains unexplained. "
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    ABSTRACT: CDKN2A at chromosome band 9p21 is the most important melanoma susceptibility gene identifi ed to date. Germline mutations of CDKN2A have been detected in melanoma families worldwide but the overall proportion of families with identifi ed mutations remains moderate. Here we applied a novel method, called multiplex ligation-dependent probe amplifi cation (MLPA), for detection of germline deletions at 9p21 in four melanoma-prone families from Latvia with no previously detected CDKN2A point mutations. No germline deletions were identifi ed, excluding 9p21 deletions as a causal event in the patients analysed. However, we describe the application of MLPA and show the advantages of the method in gene dosage analysis.
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    ABSTRACT: Although the CDKN2A gene has been shown to be the major genetic determinant governing high-penetrance susceptibility to melanoma, there remains a significant proportion of melanoma pedigrees in which germline mutations of CDKN2A have not been identified. We have therefore studied the prevalence of germline 9p deletions encompassing the CDKN2 locus in melanoma pedigrees, using multiplex ligation-dependent probe amplification. Germline deletions were found in 3 of 93 UK pedigrees, with no previously identified CDKN2A mutations. A hemizygous deletion of CDKN2A exon 1beta previously reported by this group was confirmed in one family and identified in a second. Microsatellite analysis determined that these two families were ancestrally related. In the third family, a novel p16 hemizygous deletion involving CDKN2A exons 1alpha, 2, and 3 was detected. An additional 9p21 deletion reported previously in a USA melanoma-neural system tumor family was shown to involve CDKN2A exon 1beta, and not p16. The CDKN2A exon 1beta deletions provide further evidence that this tumor suppressor gene is important in melanoma-neural system tumor susceptibility, but do not exclude the possibility of a novel gene or regulatory element also being deleted in this region. Deletions at 9p21 are rare and explain only a small proportion of melanoma susceptibility. This study is the first to comprehensively exclude deletions in melanoma-prone families with no previously identified CDKN2A mutations.
    Genes Chromosomes and Cancer 11/2005; 44(3):292-300. DOI:10.1002/gcc.20238 · 4.04 Impact Factor
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    ABSTRACT: Mutations in the CDKN2A gene underlie melanoma susceptibility in as many as 50% of melanoma kindreds in selected populations, and several CDKN2A founder mutations have been described. Inherited mutations in CDKN2A have been found to be associated with other, non-melanoma cancers including pancreatic cancer (PC) and neural system tumors (NST). Here we report a novel germline mutation in exon 1 of the CDKN2A gene, E27X, which we first detected in melanoma patients living in or originally from a small geographic area bordering Liguria in north-western Italy. A subset of melanoma kindreds positive for this mutation displayed PC and neuroblastoma. E27X generates a premature stop codon, leading to dramatically reduced protein levels of p16 and leaving p14ARF unaltered. As PC and NSTs have been postulated to be preferentially associated with CDKN2A mutations located in exon 2 and/or affecting p14ARF alone, the position of E27X in exon 1alpha provides interesting insights towards clarifying the mechanisms by which the CDKN2A/ARF locus is involved in cancer predisposition.
    Human Molecular Genetics 10/2006; 15(18):2682-9. DOI:10.1093/hmg/ddl199 · 6.39 Impact Factor
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