Department of Surgery and Department of Biochemistry and Molecular Biology, University of Southern California, USC Epigenome Center, Los Angeles, California 90089-9601, USA.
Genome Res. 2012 Feb;22(2):271-82. doi: 10.1101/gr.117523.110. Epub 2011 Jun 9.
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 ∼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.
结直肠癌（CRC）是一种异质性疾病，其独特的亚型具有不同的遗传和表观遗传改变。在这里，我们对 125 例结直肠肿瘤和 29 例相邻正常组织进行了全面的基因组规模 DNA 甲基化谱分析。我们使用基于模型的聚类分析方法鉴定了 CRC 的四个基于 DNA 甲基化的亚组。每个亚型都表现出独特的遗传和临床特征，表明它们代表了生物学上不同的亚组。CIMP-高（CIMP-H）亚组表现出异常高的癌症特异性 DNA 高甲基化频率，与 MLH1 DNA 高甲基化和 BRAF(V600E)突变密切相关。CIMP-低（CIMP-L）亚组富含 KRAS 突变，其特征是 CIMP-H 相关标记物的一部分发生 DNA 高甲基化，而不是一组独特的 CpG 岛。非 CIMP 肿瘤分为两个不同的簇。一个非 CIMP 亚组的特征是 TP53 突变频率显著升高，并且经常发生在远端结肠，而属于第四组的肿瘤则具有较低的癌症特异性 DNA 高甲基化和基因突变频率，并且显著富集直肠肿瘤。此外，我们鉴定了 112 个在 CIMP-H 肿瘤中下调超过两倍且伴有启动子 DNA 高甲基化的基因。这些代表了 CIMP-H 肿瘤中获得启动子 DNA 甲基化的基因的约 7%。有趣的是，在非 CIMP 亚组中，48/112 个基因也表现出转录下调，但这并不是由于启动子 DNA 高甲基化所致。总之，我们鉴定了 CRC 的四个不同的 DNA 甲基化亚组，并提供了关于 CIMP 特异性 DNA 高甲基化在基因沉默中的作用的新见解。
