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

Journal of Investigative Dermatology (Impact Factor: 6.37). 03/2004; 122(2):450-1. DOI: 10.1046/j.0022-202X.2004.22222.x
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    ABSTRACT: VHL is mutated in the majority of patients with clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent studies have identified recurrent mutations in histone modifying and chromatin remodeling genes, including BAP1, PBRM1, SETD2, KDM6A, and JARID1c. Current evidence suggests that BAP1 mutations are associated with aggressive disease. The clinical significance of the remaining genes is unknown. In this study, targeted sequencing of VHL and JARID1c (entire genes) and coding regions of BAP1, PBRM1, SETD2, and KDM6A was performed on 132 ccRCCs and matched normal tissues. Associations between mutations and clinical and pathological outcomes were interrogated. Inactivation of VHL (coding mutation or promoter methylation) was seen in 75% of ccRCCs. Somatic noncoding VHL alterations were identified in 29% of ccRCCs and may be associated with improved overall survival. BAP1 (11%), PBRM1 (33%), SETD2 (16%), JARID1c (4%), and KDM6A (3%) mutations were identified. BAP1-mutated tumors were associated with metastatic disease at presentation (P = 0.023), advanced clinical stage (P = 0.042) and a trend towards shorter recurrence free survival (P = 0.059) when compared with tumors exclusively mutated for PBRM1. Our results support those of recent publications pointing towards a role for BAP1 and PBRM1 mutations in risk stratifying ccRCCs. Further investigation of noncoding alterations in VHL is warranted. © 2013 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 01/2014; 53(1). DOI:10.1002/gcc.22116 · 3.84 Impact Factor
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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 major locus for melanoma predisposition is the cell cycle regulatory CDKN2A gene on chromosome 9p21. However, the frequency of germline coding mutations of the CDKN2A gene is lower than expected in melanoma-prone families linked to chromosome 9p21. To investigate whether the rare IVS1+37 G/C intronic mutation of the CDKN2A gene, recently identified in a Hungarian melanoma-prone family, influences mRNA splicing regulation. CDKN2A minigenes containing the wild-type and the mutant intronic sequence were created and transfected into HeLa cells with the aim of studying the mRNA transcripts. The results revealed the emergence of a differential splicing pattern from the wild-type and the mutant minigene, suggesting that this mutation may alter the splicing of CDKN2A primary mRNA and therefore might have a pathogenetic role in familial melanoma. We believe that these results confirm the importance of the identification and characterization of CDKN2A intronic mutations with a view to improving our understanding of the pathogenesis, and explain why the frequency of germline coding mutations of the CDKN2A gene is lower than expected in melanoma-prone families linked to chromosome 9p21.
    British Journal of Dermatology 01/2012; 167(1):131-3. DOI:10.1111/j.1365-2133.2012.10864.x · 4.10 Impact Factor


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