Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, NY, USA.
Epigenetics. 2013 Jan;8(1):34-43. doi: 10.4161/epi.23062. Epub 2012 Dec 3.
Hepatocellular carcinoma (HCC) incidence has increased in the US and also has one of the fastest growing death rates of any cancer. The purpose of the current study was to discover novel genome-wide aberrant DNA methylation patterns in HCC tumors that are predominantly HCV-related. Infinium HumanMethylation 450K BeadChip arrays were used to examine genome-wide DNA methylation profiles in 66 pairs of HCC tumor and adjacent non-tumor tissues. After Bonferroni adjustment, a total of 130,512 CpG sites significantly differed in methylation level in tumor compared with non-tumor tissues, with 28,017 CpG sites hypermethylated and 102,495 hypomethylated in tumor tissues. Absolute tumor/non-tumor methylation differences ≥ 20% were found in 24.9% of the hypermethylated and 43.1% of the hypomethylated CpG sites; almost 10,000 CpG sites have ≥ 30% DNA methylation differences. Most (60.1%) significantly hypermethylated CpG sites are located in CpG islands, with 21.6% in CpG shores and 3.6% in shelves. In contrast, only a small proportion (8.2%) of significantly hypomethylated CpG sites are situated in islands, while most are found in open sea (60.2%), shore (17.3%) or shelf (14.3%) regions. A total of 2,568 significant CpG sites (2,441 hypermethylated and 127 hypomethylated) covering 589 genes are located within 684 differentially methylated regions defined as regions with at least two significant CpG sites displaying > 20% methylation differences in the same direction within 250-bp. The top 500 significant CpG sites can significantly distinguish HCC tumor from adjacent tissues with one misclassification. Within adjacent non-tumor tissues, we also identified 75 CpG sites significantly associated with gender, 228 with HCV infection, 17,207 with cirrhosis, and 56 with both HCV infection and cirrhosis after multiple comparisons adjustment. Aberrant DNA methylation profiles across the genome were identified in tumor tissues from US HCC cases that are predominantly related to HCV infection. These results demonstrate the significance of aberrant DNA methylation in HCC tumorigenesis.
肝细胞癌（HCC）的发病率在美国有所增加，并且是癌症死亡率增长最快的癌症之一。本研究的目的是发现主要与 HCV 相关的 HCC 肿瘤中新颖的全基因组异常 DNA 甲基化模式。使用 Infinium HumanMethylation 450K BeadChip 阵列检查 66 对 HCC 肿瘤与相邻非肿瘤组织的全基因组 DNA 甲基化谱。经过 Bonferroni 调整后，与非肿瘤组织相比，肿瘤组织中共有 130512 个 CpG 位点的甲基化水平显着不同，其中 28017 个 CpG 位点呈高甲基化，102495 个 CpG 位点呈低甲基化。在高甲基化和低甲基化的 CpG 位点中，肿瘤组织与非肿瘤组织之间的绝对肿瘤/非肿瘤甲基化差异≥20%的 CpG 位点分别为 24.9%和 43.1%；几乎有 10000 个 CpG 位点的 DNA 甲基化差异≥30%。大多数（60.1%）显着高甲基化的 CpG 位点位于 CpG 岛，21.6%位于 CpG 海岸，3.6%位于支架上。相比之下，只有一小部分（8.2%）显着低甲基化的 CpG 位点位于岛屿上，而大部分位于开阔海域（60.2%），海岸（17.3%）或支架（14.3%）区域。共有 2568 个显着的 CpG 位点（2441 个高甲基化和 127 个低甲基化）覆盖 589 个基因，位于至少有两个显着 CpG 位点的 684 个差异甲基化区域内，这些区域内的 CpG 位点在 250-bp 内显示出同一方向的 >20%的甲基化差异。前 500 个显着的 CpG 位点可以用一个错分类来显着区分 HCC 肿瘤与相邻组织。在相邻的非肿瘤组织中，我们还发现了 75 个与性别显着相关的 CpG 位点，228 个与 HCV 感染显着相关，17207 个与肝硬化显着相关，56 个与 HCV 感染和肝硬化均显着相关。在美国 HCC 病例中，肿瘤组织中鉴定出了全基因组的异常 DNA 甲基化图谱，这些图谱主要与 HCV 感染有关。这些结果表明异常 DNA 甲基化在 HCC 肿瘤发生中的重要性。
