Aberrant methylation of the 5′ CpG island of TSLC1 is common in pancreatic ductal adenocarcinoma and is first manifest in high-grade PanINs
Aberrant methylation of the 5′ CpG island of TSLC1 is common in pancreatic ductal adenocarcinoma and is first manifest in high-grade PanINs
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DOI：
10.4161/cbt.84
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发表时间：
2002-05-01
影响因子：
3.6
通讯作者：
Goggins, M
中科院分区：
文献类型：
--
作者：
Jansen, M;Fukushima, N;Goggins, M
最近发现的肿瘤抑制基因TSLC 1在染色体11q23.2上经常在人类非小细胞肺腺癌中通过DNA甲基化相关沉默而失活。本研究的目的是确定TSLC 1是否在胰腺腺癌中失活。我们通过甲基化特异性PCR分析了17个胰腺癌细胞系、91个原发性胰腺癌、46个胰腺上皮内（PanIN）前体病变和15个显微镜下正常胰腺的TSLC 1基因5' CpG岛甲基化。我们在17个细胞系中的4个（24%）中观察到TSLC 1的5' CpG甲基化。在每种细胞系中，通过RT-PCR检测，异常甲基化与TSLC 1表达丧失相关，这在用DNA甲基转移酶抑制剂5-氮杂-2 '-脱氧胞苷处理后是可逆的。此外，我们观察到TSLC 1在91例原发性胰腺癌中的25例（27%）和7例高级别PanIN-3病变中的2例（29%）中甲基化，但在低级别PanIN（9例PanIN-2中的0例和30例PanIN-1中的0例）病变或正常胰腺（n=15）中未甲基化。我们的结论是，通过5' CpG岛相关甲基化的TSLC 1表达的表观遗传沉默在胰腺癌中是常见的，并且是胰腺肿瘤发展的晚期事件。
The recently identified tumor-suppressor gene TSLC1 on chromosome 11q23.2 is frequently inactivated in human non-small cell lung adenocarcinoma by DNA methylation-associated silencing. The aim of this study was to determine if TSLC1 is inactivated in adenocarcinoma of the pancreas. We analyzed 17 pancreatic cancer cell lines, 91 primary pancreatic adenocarcinoma, 46 pancreatic intraepithelial (PanIN) precursor lesions and 15 microscopically normal pancreata for methylation of the 5' CpG island of the TSLC1 gene through methylation-specific PCR. We observed 5' CpG methylation of TSLC1 in 4 of 17 cell lines (24%). In each cell line the aberrant methylation was associated with loss of TSLC1 expression by RT-PCR that was reversible after treatment with the DNA methyltransferase inhibitor 5-aza-2'- deoxycytidine. Furthermore, we observed that TSLC1 was methylated in 25 of 91 primary pancreatic adenocarcinomas (27%), and in 2 of 7 high-grade PanIN-3 lesions (29%), but not in low-grade PanIN (0 of 9 PanIN-2 and 0 of 30 PanIN-1) lesions or in normal pancreata (n=15). We conclude that epigenetic silencing of TSLC1 expression through 5' CpG island associated methylation is common in pancreatic adenocarcinoma and is a late event in pancreatic neoplastic development.