Epigenetic inactivation of DLC-1 in supratentorial primitive neuroectodermal tumor

被引:33
作者
Pang, JCS
Chang, Q
Chung, YF
Teo, JGC
Poon, WS
Zhou, LF
Kong, XY
Ng, HK [1 ]
机构
[1] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Anat & Cellular Pathol, Hong Kong, Hong Kong, Peoples R China
[2] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Surg, Hong Kong, Hong Kong, Peoples R China
[3] Fudan Univ, Huashan Hosp, Shanghai, Peoples R China
[4] Chinese Acad Sci, Inst Biol Sci, Hlth Sci Ctr, Shanghai, Peoples R China
[5] Shanghai Med Univ 2, Shanghai, Peoples R China
关键词
supratentorial primitive neuroectodermal tumor; medulloblastoma; DLC-1; hypermethylation; transcriptional silencing; epigenetics;
D O I
10.1016/j.humpath.2004.09.021
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Supratentorial primitive neuroectodermal tumors (SPNETs) and medulloblastomas (MBs) are histologically similar intracranial tumors found in different anatomic locations of the brain. Our group has previously demonstrated that loss of chromosome 8p is a frequent event in MBs. The aim of this study was to evaluate whether DLC-1, a newly identified tumor-suppressor gene on chromosome 8p22, is involved in the turnorigenesis of MBs and the histologically similar SPNETs. We first assessed for alterations of gene expression in microdissected tumors and detected lack of DIG] transcript in 1 of 9 MBs (case M44) and I of 3 SPNETs (case M 1). Neither somatic base substitutions nor homozygous deletion were found in tumors without DLC-1 transcript. We then explored the possibility of hypermethylation of the CpG island in DLC-1 as the mechanism of suppressed expression. Methylation-specific polymerase chain reaction revealed promotor hypermethylation of DLC-1 in M1 but not in M44. Bisulfite sequencing further verified a densely methylated pattern of 35 CpG sites studied in M1 that were not found in normal brain, indicating that inactivation of DLC-1 by hypermethylation is involved in SPNET. Based on this finding, we examined an additional 20 MBs, 8 SPNETs, and 4 MB and 2 SPNET cell lines for hypermethylation of the CpG island of DLC-1, finding that none of these samples exhibited DLC-1 methylation. In conclusion, our results demonstrate that transcriptional silencing of DLC-1 through promoter hypermethylation may contribute to tumorigenesis in a subset of SPNETs, and that loss of DLC-1 expression in MBs may be related to mechanisms other than promoter hypemiethylation, genomic deletion, and mutation. (C) 2005 Elsevier Inc. All rights reserved.
引用
收藏
页码:36 / 43
页数:8
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