Kim Young-Ho, Petko Zsolt, Dzieciatkowski Slavomir, Lin Li, Ghiassi Mahan, Stain Steve, Chapman William C, Washington Mary Kay, Willis Joseph, Markowitz Sanford D, Grady William M
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Genes Chromosomes Cancer. 2006 Aug;45(8):781-9. doi: 10.1002/gcc.20341.
Genetic alterations occur during the adenoma-carcinoma sequence of colon cancer formation and drive the initiation and progression of colon cancer formation. The aberrant methylation of genes is an alternate, epigenetic mechanism for silencing tumor suppressor genes in colon cancer. The aim of this study was to determine on a global and gene-specific level the role of CpG island methylation in the initiation and progression of colon cancer. Consequently, we assessed the frequency of gene methylation in tumors representative of the commonly recognized histological steps of the adenoma-carcinoma progression sequence through the analysis of eight genes previously identified to be methylated in colon cancer, MGMT, HLTF, MLH1, p14(ARF), CDKN2A, TIMP3, THBS1, and CDH1. We observed that the proportion of tumors carrying methylated alleles increased from adenomas to adenocarcinomas but that the proportion of tumors with methylated alleles was not different between adenocarcinomas and metastases (69% versus 90%, P = 0.01 and 90% versus 81%, P > 0.05). The most substantial difference occurred between early and advanced adenomas (47% versus 84%, P = 0.018). Furthermore, we observed that the frequency of gene methylation at the different steps of the progression sequence varied between genes. Thus, the aberrant methylation of genes appears to increase most significantly during the progression of early adenomas to advanced adenomas, and the frequency of specific gene methylation at the different steps of the adenoma-carcinoma progression sequence varies in a gene-specific fashion.
基因改变发生在结肠癌形成的腺瘤-癌序列过程中，并驱动结肠癌的起始和进展。基因的异常甲基化是结肠癌中使肿瘤抑制基因沉默的一种替代的表观遗传机制。本研究的目的是在全基因组和基因特异性水平上确定CpG岛甲基化在结肠癌起始和进展中的作用。因此，我们通过分析先前确定在结肠癌中发生甲基化的八个基因MGMT、HLTF、MLH1、p14(ARF)、CDKN2A、TIMP3、THBS1和CDH1，评估了腺瘤-癌进展序列中常见公认组织学阶段代表性肿瘤中的基因甲基化频率。我们观察到，携带甲基化等位基因的肿瘤比例从腺瘤到腺癌增加，但腺癌和转移癌之间携带甲基化等位基因的肿瘤比例没有差异(69%对90%，P = 0.01；90%对81%，P>0.05)。最显著的差异发生在早期和晚期腺瘤之间(47%对84%，P = 0.018)。此外，我们观察到进展序列不同阶段的基因甲基化频率在不同基因之间有所不同。因此，基因的异常甲基化似乎在早期腺瘤进展为晚期腺瘤的过程中增加最为显著，并且腺瘤-癌进展序列不同阶段的特定基因甲基化频率以基因特异性方式变化。
