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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Available from: Silvia Majore, Nov 28, 2015
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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: The most common genetic determinants of skin cancer are the genes that control skin color so that the genes expressed as black skin are protective. Within the white population variants at the MC1R locus are shown to increase susceptibility, and recent evidence suggests that polymorphisms in the OCA2 gene interact to modify risk. Other as-yet-unidentified pigment genes may also play a role in susceptibility to melanoma. Thus MC1R variants are the most common low-penetrance melanoma-susceptibility genes so far identified. Other putative low-penetrance susceptibility genes have been explored using candidate gene approaches. Good candidates such as the DNA repair gene XRCC3 and polymorphisms of EGF have been studied but excluded. Other candidates such as BRAF polymorphisms and variants at the CDKN2A locus remain to be fully investigated. More progress has been made in identifying high-penetrance genes, however. The most common (and probably the most penetrant) susceptibility locus is the CDKN2A locus coding for two tumor suppressor proteins, p16 and p14ARF. Mutations at this locus that impact p16, p14ARF or both proteins all increase susceptibility to melanoma. Families inheriting such mutants are at increased risk of cutaneous melanoma, and the penetrance is increased by residence in sunny climates and co-inheritance of MC1R variants. Some families also appear to be at increased risk of pancreatic cancer, but the determinants of susceptibility to pancreatic cancer are not yet understood. Very rare families have germline mutations in the CDK4 gene which impact on the p16 binding site. There are other high-penetrance susceptibility genes, however, which remain undiscovered. There is evidence of one at 1p22. The Melanoma Genetics Consortium ( continues to explore this and the genetic epidemiology of the CDKN2A locus.
    Drugs of today (Barcelona, Spain: 1998) 04/2005; 41(3):193-203. DOI:10.1358/dot.2005.41.3.892524 · 1.20 Impact Factor
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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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