Aberrant methylation of candidate tumor suppressor genes in neuroblastoma

被引:52
作者
Hoebeeck, Jasmien [1 ]
Michels, Evi [1 ]
Pattyn, Filip [1 ]
Combaret, Valerie [2 ]
Vermeulen, Joelle [1 ]
Yigit, Nurten [1 ]
Hoyoux, Claire [3 ]
Laureys, Genevieve [4 ]
De Paepe, Anne [1 ]
Spelernan, Frank [1 ]
Vandesompele, Jo [1 ]
机构
[1] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium
[2] Ctr Leon Berard, Mol Oncol Unit, F-69373 Lyon, France
[3] Hop Citadelle, Dept Pediat Oncol, Liege, Belgium
[4] Ghent Univ Hosp, Dept Pediat Hematol & Oncol, B-9000 Ghent, Belgium
关键词
Neuroblastoma; Methylation; MSP; CPG ISLAND HYPERMETHYLATION; CANCER CELL-LINES; TIME PCR PRIMER; DNA METHYLATION; PROMOTER HYPERMETHYLATION; EPIGENETIC INACTIVATION; MULTIPLE GENES; RASSF1A GENE; EXPRESSION; IDENTIFICATION;
D O I
10.1016/j.canlet.2008.08.019
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
CpG island hypermethylation has been recognized as an alternative mechanism for tumor suppressor gene inactivation. In this study, we performed methylation-specific PCR (MSP) to investigate the methylation status of 10 selected tumor suppressor genes in neuroblastoma. Seven of the investigated genes (CD44, RASSF1A, CASP8, PTEN, ZMYND10, CDH1, PRDM2) showed high frequencies (>= 30%) of methylation in 33 neuroblastoma cell lines. In 42 primary neuroblastoma tumors, the frequencies of methylation were 69%, CD44; 71%, RASSF1A; 56%, CASP8; 25%, PTEN; 15%, ZMYND10; 8%, CDH1; and 0%, PRDM2. Furthermore, CASP8 and CDH1 hypermethylation was significantly associated with poor event-free survival. Meta-analysis of 115 neuroblastoma tumors demonstrated a significant correlation between CASP8 methylation and MYCN amplification. In addition, there was a correlation between ZMYND10 methylation and MYCN amplification. The MSP data, together with optimized mRNA re-expression experiments (in terms of concentration and time of treatment and use of proper reference genes) further strengthen the notion that epigenetic alterations could play a significant role in NB oncogenesis. This study thus warrants the need for a global profiling of gene promoter hypermethylation to identify genome-wide aberrantly methylated genes in order to further understand neuroblastoma pathogenesis and to identify prognostic methylation markers. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:336 / 346
页数:11
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