Elucidating the Landscape of Aberrant DNA Methylation in Hepatocellular Carcinoma

Abstract

BackgroundHepatocellular carcinoma (HCC) is one of the most common cancers and frequently presents with an advanced disease at diagnosis. There is only limited knowledge of genome-scale methylation changes in HCC.Methods and FindingsWe performed genome-wide methylation profiling in a total of 47 samples including 27 HCC and 20 adjacent normal liver tissues using the Illumina HumanMethylation450 BeadChip. We focused on differential methylation patterns in the promoter CpG islands as well as in various less studied genomic regions such as those surrounding the CpG islands, i.e. shores and shelves. Of the 485,577 loci studied, significant differential methylation (DM) was observed between HCC and adjacent normal tissues at 62,692 loci or 13% (p<1.03e-07). Of them, 61,058 loci (97%) were hypomethylated and most of these loci were located in the intergenic regions (43%) or gene bodies (33%). Our analysis also identified 10,775 differentially methylated (DM) loci (17% out of 62,692 loci) located in or surrounding the gene promoters, 4% of which reside in known Differentially Methylated Regions (DMRs) including reprogramming specific DMRs and cancer specific DMRs, while the rest (10,315) involving 4,106 genes could be potential new HCC DMR loci. Interestingly, the promoter-related DM loci occurred twice as frequently in the shores than in the actual CpG islands. We further characterized 982 DM loci in the promoter CpG islands to evaluate their potential biological function and found that the methylation changes could have effect on the signaling networks of Cellular development, Gene expression and Cell death (p = 1.0e-38), with BMP4, CDKN2A, GSTP1, and NFATC1 on the top of the gene list.ConclusionSubstantial changes of DNA methylation at a genome-wide level were observed in HCC. Understanding epigenetic changes in HCC will help to elucidate the pathogenesis and may eventually lead to identification of molecular markers for liver cancer diagnosis, treatment and prognosis.

Alteration of Epigenetic Profile in Human Hepatocellular Carcinoma and Its Clinical Implications

“…In contrast, the majority of hypomethylated CpGs in HCC were located away from CpG islands. Another group also reported that hypermethylated CpGs were mainly distributed close to transcription start sites, and the majority of hypomethylated CpGs were observed within 3′ regions of genes and intragenic regions [18]. …”

Epigenetic alterations in endocrine-related cancer

“…Absent or diminished expression of the GSTP1 gene in prostate cancer has been reported and is commonly due to CpG island GSTP1 promoter region methylation in the majority of prostate tumors (O90%), a phenomenon that is rarely detected in normal prostate or benign prostatic hyperplasia tissues. This gene has also been described as hypermethylated in breast carcinoma, an early event, which suggests its utility as a biomarker (Mahapatra et al 2012, Saxena et al 2012, Fukushige & Horii 2013, Song et al 2013. The DNA alkyl-repair gene MGMT, which removes mutagenic and cytotoxic alkyl adducts from genomic DNA, has also been found hypermethylated in this type of tumor (Kang et al 2004; Table 1).…”

Epigenetics in Liver Disease

“…A study of hepatitis B virus (HBV)-induced HCC compared DNA methylation profiles between tumor and adjacent tissue, this identified 1,640 hypomethylated and 684 hypermethylated CpG in the tumor. 14 Using a similar approach, Song et al 15 reported that 62,692 loci displayed differential methylation between HCC and surrounding tissue, of which a remarkable 61,058 were hypomethylated. In a more focused study, tumor suppressor genes were identified that are hypermethylated in the early stages of HCC.…”