Abe Masanobu, Watanabe Naoko, McDonell Nathalie, Takato Tsuyoshi, Ohira Miki, Nakagawara Akira, Ushijima Toshikazu
Carcinogenesis Division, National Cancer Center Research Institute, Tokyo, Japan.
Oncology. 2008;74(1-2):50-60. doi: 10.1159/000139124. Epub 2008 Jun 11.
BACKGROUND/AIMS: CpG island (CGI) methylator phenotype (CIMP) is strongly associated with poor prognosis in neuroblastomas (NBLs; hazard ratios 7-22). Methylation of nonpromoter CGIs is useful to detect the presence of the CIMP, while the poor prognosis is considered to be caused by gene silencing due to promoter methylation. Here, promoter CGIs targeted by the CIMP were searched for.
A genome-wide screening was performed by methylation-sensitive representational difference analysis of CIMP(+) and CIMP(-) NBLs.
Promoter CGIs of 9 genes were methylated in CIMP(+) NBL cell lines and caused silencing of their downstream genes. On analysis of 90 clinical specimens, CYP26C1,FERD3L (N-TWIST), CRYBA2 and PCDHGC4 were methylated at significantly higher incidences in CIMP(+) NBLs than CIMP(-) NBLs, while the difference was unclear for NPY, SPAG6, DDIT4L, CHR3SYT and C6Orf141. Methylation of CYP26C1 and FERD3L was significantly associated with poor prognosis, but weaker than the presence of the CIMP. Treatment of an NBL cell line with a demethylating agent caused demethylation of multiple promoter CGIs, and enhanced 13-cis-retinoic acid-induced neuronal differentiation.
Our results indicate that the CIMP causes poor prognosis of NBLs by inducing methylation of multiple promoter CGIs with various incidences.
背景/目的：CpG岛（CGI）甲基化表型（CIMP）与神经母细胞瘤（NBL）的不良预后密切相关（风险比为7 - 22）。非启动子CGI的甲基化有助于检测CIMP的存在，而不良预后被认为是由启动子甲基化导致的基因沉默引起的。在此，我们搜索了受CIMP靶向的启动子CGI。
通过对CIMP（+）和CIMP（-）NBL进行甲基化敏感的代表性差异分析进行全基因组筛选。
9个基因的启动子CGI在CIMP（+）NBL细胞系中发生甲基化，并导致其下游基因沉默。在对90份临床标本的分析中，CYP26C1、FERD3L（N - TWIST）、CRYBA2和PCDHGC4在CIMP（+）NBL中的甲基化发生率显著高于CIMP（-）NBL，而NPY、SPAG6、DDIT4L、CHR3SYT和C6Orf141的差异不明显。CYP26C1和FERD3L的甲基化与不良预后显著相关，但弱于CIMP的存在。用去甲基化剂处理NBL细胞系会导致多个启动子CGI去甲基化，并增强13 - 顺式维甲酸诱导的神经元分化。
我们的结果表明，CIMP通过诱导多个启动子CGI以不同发生率发生甲基化，导致NBL预后不良。
