Genome-scale analysis of aberrant DNA methylation in colorectal cancer
Genome-scale analysis of aberrant DNA methylation in colorectal cancer
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DOI：
10.1101/gr.117523.110
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发表时间：
2012-02-01
期刊：
影响因子：
7
通讯作者：
Laird, Peter W.
中科院分区：
文献类型：
--
作者：
Hinoue, Toshinori;Weisenberger, Daniel J.;Laird, Peter W.
结直肠癌（CRC）是一种异质疾病，其中独特的亚型的特征是不同的遗传和表观遗传学改变。在这里，我们对125个结直肠肿瘤和29个相邻正常组织进行了全面的基因组尺度DNA甲基化分析。我们使用基于模型的集群分析确定了CRC的四个基于DNA甲基化的亚组。每个亚型都显示出特征性的遗传和临床特征，表明它们代表生物学上不同的亚组。 CIMP高（CIMP-H）亚组表现出极高的癌症特异性DNA高甲基化频率，与MLH1 DNA高甲基化和BRAF（V600E）突变密切相关。 CIMP-low（CIMP-L）亚组富含KRAS突变，并以DNA高甲基化为特征，其亚甲基化是CIMP-H相关标记的子集，而不是独特的CPG岛。非细胞肿瘤分为两个不同的簇。一个非CIMP亚组的区分是，TP53突变的频率明显更高，并且远端结肠中频繁出现，而属于第四组的肿瘤表现出癌症特异性DNA高甲基化和基因突变的低频，并且显着富集并且富集了。用于直肠肿瘤。此外，我们确定了112个基因，这些基因在CIMP-H肿瘤中与启动子DNA高甲基化一起被下调了两倍以上。这些代表类似于获得CIMP-H肿瘤中获得启动子DNA甲基化的7％的基因。有趣的是，在非CIMP亚组中也下调了48/112的基因，但这不是启动子DNA高甲基化。我们一起确定了CRC的四个不同的DNA甲基化亚组，并就CIMP特异性DNA高甲基化在基因沉默中的作用提供了新的见解。
Colorectal cancer (CRC) is a heterogeneous disease in which unique subtypes are characterized by distinct genetic and epigenetic alterations. Here we performed comprehensive genome-scale DNA methylation profiling of 125 colorectal tumors and 29 adjacent normal tissues. We identified four DNA methylation based subgroups of CRC using model-based cluster analyses. Each subtype shows characteristic genetic and clinical features, indicating that they represent biologically distinct subgroups. A CIMP-high (CIMP-H) subgroup, which exhibits an exceptionally high frequency of cancer-specific DNA hypermethylation, is strongly associated with MLH1 DNA hypermethylation and the BRAF(V600E) mutation. A CIMP-low (CIMP-L) subgroup is enriched for KRAS mutations and characterized by DNA hypermethylation of a subset of CIMP-H-associated markers rather than a unique group of CpG islands. Non-CIMP tumors are separated into two distinct clusters. One non-CIMP subgroup is distinguished by a significantly higher frequency of TP53 mutations and frequent occurrence in the distal colon, while the tumors that belong to the fourth group exhibit a low frequency of both cancer-specific DNA hypermethylation and gene mutations and are significantly enriched for rectal tumors. Furthermore, we identified 112 genes that were down-regulated more than twofold in CIMP-H tumors together with promoter DNA hypermethylation. These represent similar to 7% of genes that acquired promoter DNA methylation in CIMP-H tumors. Intriguingly, 48/112 genes were also transcriptionally down-regulated in non-CIMP subgroups, but this was not attributable to promoter DNA hypermethylation. Together, we identified four distinct DNA methylation subgroups of CRC and provided novel insight regarding the role of CIMP-specific DNA hypermethylation in gene silencing.