Differences in DNA methylation signatures reveal multiple pathways of progression from adenoma to colorectal cancer.
Differences in DNA methylation signatures reveal multiple pathways of progression from adenoma to colorectal cancer.
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DOI：
10.1053/j.gastro.2014.04.039
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发表时间：
2014-08
期刊：
影响因子：
29.4
通讯作者：
Grady WM
中科院分区：
文献类型：
--
作者：
Luo Y;Wong CJ;Kaz AM;Dzieciatkowski S;Carter KT;Morris SM;Wang J;Willis JE;Makar KW;Ulrich CM;Lutterbaugh JD;Shrubsole MJ;Zheng W;Markowitz SD;Grady WM
基因和表观遗传改变参与了结直肠癌的发病机制。结直肠肿瘤之间存在着相当大的分子异质性，这似乎是随着息肉进展为癌症而出现的。这种异质性导致了不同的肿瘤发生途径。虽然在传统的管状腺瘤中已经检测到表观遗传和遗传改变，但关于这些改变如何影响进展到结直肠癌，我们知之甚少。我们比较了正常结肠粘膜、管状腺瘤和结直肠癌的甲基组，以确定表观遗传改变可能如何促进癌症的形成。我们对41例正常结肠组织、42例结肠腺瘤和癌组织进行了基于全基因组阵列的研究和全面的数据分析。我们发现，在管状腺瘤和癌症附近的非肿瘤结肠粘膜中，DNA甲基化发生了全基因组的变化。根据DNA甲基化模式识别出三类癌和两类腺瘤。腺瘤分为高频甲基化(腺瘤-H)和低频甲基化(腺瘤-L)。在腺瘤-H类中，腺瘤的一个子集具有突变的KRAS。此外，腺瘤-H类的DNA甲基化特征类似于低或中等甲基化水平的癌症，而腺瘤-L类的甲基化特征类似于非肿瘤结肠组织。在这些标记中差异甲基化的CPGS位点位于基因内区和基因间区。DNA甲基化的全基因组改变发生在管状腺瘤向癌症进展的早期阶段。这些发现揭示了结直肠癌发病机制的异质性，甚至在结直肠癌的腺瘤阶段也是如此。
Genetic and epigenetic alterations contribute to the pathogenesis of colorectal cancer (CRC). There is considerable molecular heterogeneity among colorectal tumors, which appears to arise as polyps progress to cancer. This heterogeneity results in different pathways to tumorigenesis. Although epigenetic and genetic alterations have been detected in conventional tubular adenomas, little is known about how these affect progression to CRC. We compared methylomes of normal colon mucosa, tubular adenomas, and colorectal cancers to determine how epigenetic alterations might contribute to cancer formation. We conducted genome-wide array-based studies and comprehensive data analyses of aberrantly methylated loci in 41 normal colon tissue, 42 colon adenomas, and 64 cancers using HumanMethylation450 arrays. We found genome-wide alterations in DNA methylation in the non-tumor colon mucosa adjacent to tubular adenomas and cancers. Three classes of cancers and 2 classes of adenomas were identified based on their DNA methylation patterns. The adenomas separated into classes of high-frequency methylation (adenoma-H), and low-frequency methylation (adenoma-L). Within the adenoma-H class a subset of adenomas had mutant KRAS. Additionally, the adenoma-H class had DNA methylation signatures similar to those of cancers with low or intermediate levels of methylation, whereas the adenoma-L class had methylation signatures similar to that of non-tumor colon tissue. The CpGs sites that were differentially methylated in these signatures are located in intragenic and intergenic regions. Genome-wide alterations in DNA methylation occur during early stages of progression of tubular adenomas to cancer. These findings reveal heterogeneity in the pathogenesis of colorectal cancer, even at the adenoma step of the process.
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影响因子：
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作者：
Dedeurwaerder, Sarah;Defrance, Matthieu;Fuks, Francois
通讯作者：
Fuks, Francois
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