Abstract
Genome-wide analysis is widely applied to detect molecular alterations during oncogenesis and tumor progression. We analyzed DNA methylation profiles of hepatocellular carcinoma (HCC), and investigated the clinical role of most heypermethylated of tumor, encodes T-box 15 (TBX15), which was originally involved in mesodermal differentiation. We conducted a genome-wide analysis of DNA methylation of tumor and non-tumor tissue of 15 patients with HCC, and revealed TBX15 was the most hypermethylated gene of tumor (Beta-value in tumor tissue = 0.52 compared with non-tumor tissue). Another validation set, which comprised 58 HCC with radical resection, was analyzed to investigate the relationships between tumor phenotype and TBX15 mRNA expression. TBX15 mRNA levels in tumor tissues were significantly lower compared with those of nontumor tissues (p < 0.0001). When we assigned a cutoff value = 0.5-fold, the overall survival 5-year survival rates of the low-expression group (n = 17) were significantly shorter compared with those of the high-expression group (n = 41) (43.3% vs. 86.2%, p = 0.001). Multivariate analysis identified low TBX15 expression as an independent prognostic factor for overall and disease-free survival. Therefore, genome-wide DNA methylation profiling indicates that hypermethylation and reduced expression of TBX15 in tumor tissue represents a potential biomarker for predicting poor survival of patients with HCC.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most prevalent human cancer and third-highest cause of cancerrelated deaths worldwide, and its incidence is significantly increasing [1, 2]
We focused on the epigenetic alterations of the genomes of tumor and non-tumor cells of patients with HCC to identify the mechanisms of tumor progression and hepatocarcinogenesis., because global DNA hypomethylation or cancer specific DNA hypermethylation occurs in certain carcinomas [12]
T-box 15 (TBX15) mRNA expression in tumor tissue was varied according to type of carcinoma, while it was significantly lower in tumor tissue of HCC compared to nontumor tissue (Supplementary Figure 3)
Summary
Hepatocellular carcinoma (HCC) is the sixth most prevalent human cancer and third-highest cause of cancerrelated deaths worldwide, and its incidence is significantly increasing [1, 2]. Several genome-wide studies of the molecular alterations in tumor and non-tumor liver tissues addressed DNA, mRNA, and microRNA (miRNA) expression as well as epigenetic alterations to predict recurrence and hepatocarcinogenesis after treating patients with curative intent according to distinct gene expression or alteration patterns [7,8,9,10,11]. We focused on the epigenetic alterations of the genomes of tumor and non-tumor cells of patients with HCC to identify the mechanisms of tumor progression and hepatocarcinogenesis., because global DNA hypomethylation or cancer specific DNA hypermethylation occurs in certain carcinomas [12]. We investigated epigenetic characteristics with array-based analysis of DNA methylation using the Illumina Human Methylation 450 BeadChip, and identified specific DNA methylation profiling in nontumor liver tissue of patients without HCV and HBV detectable infection (NBNCHCC), which possibly contributed to the development of HCC [14].
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