SILENCING OF THE VHL TUMOR-SUPPRESSOR GENE BY DNA METHYLATION IN RENAL-CARCINOMA
SILENCING OF THE VHL TUMOR-SUPPRESSOR GENE BY DNA METHYLATION IN RENAL-CARCINOMA
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DOI：
10.1073/pnas.91.21.9700
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发表时间：
1994-10-11
影响因子：
11.1
通讯作者：
BAYLIN, SB
中科院分区：
文献类型：
--
作者：
HERMAN, JG;LATIF, F;BAYLIN, SB
VHL基因的突变失活和等位基因丢失似乎是大多数自发性肾透明细胞癌的原因。我们现在表明，在5'区的一个正常的非甲基化的CPG岛的超甲基化提供了另一个潜在的重要机制，在这些癌症的显着部分的VHL基因的失活。在检查的26个肿瘤中的5个（19%）中发现了这种超甲基化。其中四个已经失去了一个拷贝的VHL，而一个保留了两个高度甲基化的等位基因。四个VHL高甲基化的肿瘤没有检测到突变，而一个除了单一保留等位基因的高甲基化外还有错义突变。正如在该5' CpG岛中甲基化的结果所预测的，5个肿瘤中没有一个表达VHL基因。相反，正常肾脏和所有检测到失活VHL基因突变但没有CpG岛甲基化的肿瘤均有表达。在肾细胞培养系中，用5-氮杂-2 '-脱氧胞苷处理导致VHL基因的再表达。这些发现表明，CpG岛的异常甲基化可能参与肿瘤抑制基因的失活，启动或导致人类常见癌症的进展。
Mutational inactivation and allelic loss of the von Hippel-Lindan (VHL) gene appear to be causal events for the majority of spontaneous clear-cell renal carcinomas. We now show that hypermethylation of a normally unmethylated CPG island in the 5' region provides another potentially important mechanism for inactivation of the VHL gene in a significant portion of these cancers. This hypermethylation was found in 5 of 26 (19%) tumors examined. Four of these had lost one copy of VHL while one retained two heavily methylated alleles. Four of the tumors with VHL hypermethylation had no detectable mutations, whereas one had a missense mutation in addition to hypermethylation of the single retained allele. As would be predicted for the consequence of methylation in this 5' CpG island, none of the 5 tumors expressed the VHL gene. In contrast, normal kidney and all tumors examined with inactivating VHL gene mutations but no CpG island methylation had expression. In a renal cell culture line, treatment with 5-aza-2'-deoxycytidine resulted in reexpression of the VHL gene. These findings suggest that aberrant methylation of CpG islands may participate in the tumor-suppressor gene inactivations which initiate or cause progression of common human cancers.