Abstract
The majority of the epigenomic reports in hepatocellular carcinoma have focused on identifying novel differentially methylated drivers or passengers of the oncogenic process. Few reports have considered the technologies in place for clinical translation of newly identified biomarkers. The aim of this study was to identify epigenomic technologies that need only a small number of samples to discriminate HCC from non-HCC tissue, a basic requirement for biomarker development trials. To assess that potential, we used quantitative Methylation Specific PCR, oligonucleotide tiling arrays, and Methylation BeadChip assays. Concurrent global DNA hypomethylation, gene-specific hypermethylation, and chromatin alterations were observed as a hallmark of HCC. A global loss of promoter methylation was observed in HCC with the Illumina BeadChip assays and the Nimblegen oligonucleotide arrays. HCC samples had lower median methylation peak scores and a reduced number of significant promoter-wide methylated probes. Promoter hypermethylation of RASSF1A, SSBP2, and B4GALT1 quantified by qMSP had a sensitivity ranging from 38% to 52%, a specificity of 100%, and an AUC from 0.58 to 0.75. A panel combining these genes with HCC risk factors had a sensitivity of 87%, a specificity of 100%, and an AUC of 0.91.
Highlights
Promoter-wide alterations of DNA methylation have been described at all stages that encompass hepatocarcinogenesis, precancerous lesions, and tumor initiation to unresectable HCC [1, 2], mostly focusing on aberrant hypermethylation of CpG islands in gene promoter regions near the Transcription Start Site (TSS) [3, 4]
“M” represents that a sample has a value above the quantitative MethylationSpecific PCR (qMSP) methylation threshold for that gene
“U” represent that a sample has a value below the qMSP methylation threshold for that gene
Summary
Promoter-wide alterations of DNA methylation have been described at all stages that encompass hepatocarcinogenesis, precancerous lesions, and tumor initiation to unresectable HCC [1, 2], mostly focusing on aberrant hypermethylation of CpG islands in gene promoter regions near the Transcription Start Site (TSS) [3, 4]. Several hypermethylated genes have been identified using a range of diverse technologies. The earlier methylation studies of HCC used the candidate gene approach and first generation methylation. A recent number of studies have used Methylated DNA immunoprecipitation-on-chip analysis (MeDIP-chip) [8] and BeadChip assay technologies to identify novel genes differentially methylated in HCC [9]. Most HCC methylation studies have used available technologies to profile and identify differentially methylated genes that drive the oncogenic process [10]
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