Prognostic implications of and relationship between CpG island hypermethylation and repetitive DNA hypomethylation in hepatocellular carcinoma

Hwan Seok Lee, Baek Hee Kim, Nam Yun Cho, Eun Joo Yoo, Minhee Choi, So Hyun Shin, Ja June Jang, Kyungsuk Suh, Yong Sung Kim, Gyeonghoon Kang

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Abstract

Purpose: This study aims to determine the relationship between CpG island DNA hypermeth- ylation and global genomic DNA hypomethylation and their prognostic implications in hepatocellular carcinoma. The association of DNA methylation changes with clinicopathologic factors and the chronological ordering of DNA methylation changes along multistep hepatocarcino-genesis were also assessed. Experimental Design: Hepatocellular carcinoma (n = 20) and nonneoplastic liver samples (n = 72) were analyzed for their methylation status at 41 CpG island loci and 3 repetitive DNA elements (LINE-1, ALU,and SAT2) using Methy Light or combined bisulfite restriction analysis. After selection of 19 CpG island loci showing cancer-specific DNA methylation, another set of 99 hepatocellular carcinoma samples was analyzed for these loci. Results: The number of methylated genes in hepatocellular carcinoma was significantly higher in hepatocellular carcinoma patients with a cirrhotic liver than in hepatocellular carcinoma patients with a noncirrhotic liver (9.9 versus 7.0, P = 0.001). Hepatocellular carcinoma from female patients showed a higher number of methylated genes than hepatocellular carcinoma from male patients (11.2 versus 8.4, P = 0.006). The genes CRABP1 and SYK showed significant association between CpG island hypermethylation and patients' poor survival. SAT2 hypomethylation occurred earlier than LINE-1 or ALU hypomethylation along the multistep hepatocarcinogenesis. Depending on the type of CpG island locus, a direct, inverse, or no relationship between CpG island hypermethylation and repetitive DNA hypomethylation was observed in hepatocellular carcinomas. Conclusion: The varying relationships between the hypermethylation of individual CpG island loci and the hypomethylation of repetitive elements suggests that they are not mechanically linked. SYK and CRABP1 hypermethylation may serve as useful tumor markers for prognostication of hepatocellular carcinoma patients.

Original languageEnglish
Pages (from-to)812-820
Number of pages9
JournalClinical Cancer Research
Volume15
Issue number3
DOIs
StatePublished - 1 Feb 2009

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CpG Islands
Hepatocellular Carcinoma
DNA
DNA Methylation
Liver
Long Interspersed Nucleotide Elements
Genes
Tumor Biomarkers
Methylation
Research Design
Light

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Lee, Hwan Seok ; Kim, Baek Hee ; Cho, Nam Yun ; Yoo, Eun Joo ; Choi, Minhee ; Shin, So Hyun ; Jang, Ja June ; Suh, Kyungsuk ; Kim, Yong Sung ; Kang, Gyeonghoon. / Prognostic implications of and relationship between CpG island hypermethylation and repetitive DNA hypomethylation in hepatocellular carcinoma. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 3. pp. 812-820.
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abstract = "Purpose: This study aims to determine the relationship between CpG island DNA hypermeth- ylation and global genomic DNA hypomethylation and their prognostic implications in hepatocellular carcinoma. The association of DNA methylation changes with clinicopathologic factors and the chronological ordering of DNA methylation changes along multistep hepatocarcino-genesis were also assessed. Experimental Design: Hepatocellular carcinoma (n = 20) and nonneoplastic liver samples (n = 72) were analyzed for their methylation status at 41 CpG island loci and 3 repetitive DNA elements (LINE-1, ALU,and SAT2) using Methy Light or combined bisulfite restriction analysis. After selection of 19 CpG island loci showing cancer-specific DNA methylation, another set of 99 hepatocellular carcinoma samples was analyzed for these loci. Results: The number of methylated genes in hepatocellular carcinoma was significantly higher in hepatocellular carcinoma patients with a cirrhotic liver than in hepatocellular carcinoma patients with a noncirrhotic liver (9.9 versus 7.0, P = 0.001). Hepatocellular carcinoma from female patients showed a higher number of methylated genes than hepatocellular carcinoma from male patients (11.2 versus 8.4, P = 0.006). The genes CRABP1 and SYK showed significant association between CpG island hypermethylation and patients' poor survival. SAT2 hypomethylation occurred earlier than LINE-1 or ALU hypomethylation along the multistep hepatocarcinogenesis. Depending on the type of CpG island locus, a direct, inverse, or no relationship between CpG island hypermethylation and repetitive DNA hypomethylation was observed in hepatocellular carcinomas. Conclusion: The varying relationships between the hypermethylation of individual CpG island loci and the hypomethylation of repetitive elements suggests that they are not mechanically linked. SYK and CRABP1 hypermethylation may serve as useful tumor markers for prognostication of hepatocellular carcinoma patients.",
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Prognostic implications of and relationship between CpG island hypermethylation and repetitive DNA hypomethylation in hepatocellular carcinoma. / Lee, Hwan Seok; Kim, Baek Hee; Cho, Nam Yun; Yoo, Eun Joo; Choi, Minhee; Shin, So Hyun; Jang, Ja June; Suh, Kyungsuk; Kim, Yong Sung; Kang, Gyeonghoon.

In: Clinical Cancer Research, Vol. 15, No. 3, 01.02.2009, p. 812-820.

Research output: Contribution to journalArticle

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AU - Kim, Baek Hee

AU - Cho, Nam Yun

AU - Yoo, Eun Joo

AU - Choi, Minhee

AU - Shin, So Hyun

AU - Jang, Ja June

AU - Suh, Kyungsuk

AU - Kim, Yong Sung

AU - Kang, Gyeonghoon

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AB - Purpose: This study aims to determine the relationship between CpG island DNA hypermeth- ylation and global genomic DNA hypomethylation and their prognostic implications in hepatocellular carcinoma. The association of DNA methylation changes with clinicopathologic factors and the chronological ordering of DNA methylation changes along multistep hepatocarcino-genesis were also assessed. Experimental Design: Hepatocellular carcinoma (n = 20) and nonneoplastic liver samples (n = 72) were analyzed for their methylation status at 41 CpG island loci and 3 repetitive DNA elements (LINE-1, ALU,and SAT2) using Methy Light or combined bisulfite restriction analysis. After selection of 19 CpG island loci showing cancer-specific DNA methylation, another set of 99 hepatocellular carcinoma samples was analyzed for these loci. Results: The number of methylated genes in hepatocellular carcinoma was significantly higher in hepatocellular carcinoma patients with a cirrhotic liver than in hepatocellular carcinoma patients with a noncirrhotic liver (9.9 versus 7.0, P = 0.001). Hepatocellular carcinoma from female patients showed a higher number of methylated genes than hepatocellular carcinoma from male patients (11.2 versus 8.4, P = 0.006). The genes CRABP1 and SYK showed significant association between CpG island hypermethylation and patients' poor survival. SAT2 hypomethylation occurred earlier than LINE-1 or ALU hypomethylation along the multistep hepatocarcinogenesis. Depending on the type of CpG island locus, a direct, inverse, or no relationship between CpG island hypermethylation and repetitive DNA hypomethylation was observed in hepatocellular carcinomas. Conclusion: The varying relationships between the hypermethylation of individual CpG island loci and the hypomethylation of repetitive elements suggests that they are not mechanically linked. SYK and CRABP1 hypermethylation may serve as useful tumor markers for prognostication of hepatocellular carcinoma patients.

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