This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, Y.-J. Articles by Santella, R. M. Search for Related Content PubMed PubMed Citation Articles by Zhang, Y.-J. Articles by Santella, R. M. Related Collections Related Article

Predicting Hepatocellular Carcinoma by Detection of Aberrant Promoter Methylation in Serum DNA

Authors' Affiliations: Departments of ¹ Environmental Health Sciences, ² Epidemiology, and ³ Biostatistics, Mailman School of Public Health of Columbia University, New York, New York; ⁴ Department of Statistics, National Cheng Kung University, Tainan, Taiwan; ⁵ College of Public Health, National Taiwan University; ⁶ Genomics Research Center, Academia Sinica, Taipei, Taiwan; and ⁷ Graduate Institute of Aboriginal Health, Tzu Chi University, Hualian, Taiwan

Requests for reprints: Yu-Jing Zhang, Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, 701 West 168th Street, New York, NY 10032. Phone: 212-305-8158; Fax: 212-305-5328; E-mail: yz6{at}columbia.edu.

Purpose: Most hepatocellular carcinomas (HCC) are diagnosed at an advanced stage. Hypermethylation of CpG islands in promoter regions is now recognized as an important early event in carcinogenesis and detection of methylated DNA has been suggested as a potential biomarker for early detection of cancer. There are no studies on epigenetic changes in samples from HCC patients before diagnosis. We explored the possible diagnostic value of aberrant promoter hypermethylation of three tumor suppressor genes in serum DNA for early detection of HCC.

Experimental Design: Aberrant promoter hypermethylation was investigated in DNA isolated from the serum of 50 HCC patients who provided repeated blood samples before diagnosis and 50 controls enrolled in a cancer screen program in Taiwan. Methylation-specific PCR was used to determine the methylation status of p16, p15, and ras association domain family 1A (RASSF1A).

Results: Among cases, aberrant methylation was found in serum DNA 1 to 9 years before clinical HCC diagnosis. RASSF1A had the highest frequency of hypermethylation with 35 (70%) cases having at least one positive sample compared with 22 (44%) for p16 and 12 (22%) for p15. Six subjects were hypermethylation negative for all three genes. For the 50 controls, promoter hypermethylation was found in three and two subjects for RASSF1A and p16, respectively; none had methylation of p15. A receiver operating characteristic curve that included clinical risk factors (age, HBsAg status, anti–hepatitis C virus status, smoking, and alcohol status) and hypermethylation biomarkers gave an overall predictive accuracy of 89% with sensitivity and specificity 84% and 94%, respectively.

Conclusions: The analysis of epigenetic changes on RASSF1A, p16, and p15 tumor suppressor genes in serum DNA may be a valuable biomarkers for early detection in populations at high risk of HCC.

Related Article

The Use of Epigenetic Biomarkers for Preclinical Detection of Hepatocellular Carcinoma: Potential for Noninvasive Screening of High-Risk Populations

Ashley G. Rivenbark and William B. Coleman
Clin. Cancer Res. 2007 13: 2309-2312. [Full Text] [PDF]

This article has been cited by other articles:

				Y. Pei, T. Zhang, V. Renault, and X. Zhang An overview of hepatocellular carcinoma study by omics-based methods Acta Biochim Biophys Sin, January 1, 2009; 41(1): 1 - 15. [Abstract] [Full Text] [PDF]

				K. C. A. Chan, P. B. S. Lai, T. S. K. Mok, H. L. Y. Chan, C. Ding, S. W. Yeung, and Y. M. D. Lo Quantitative Analysis of Circulating Methylated DNA as a Biomarker for Hepatocellular Carcinoma Clin. Chem., September 1, 2008; 54(9): 1528 - 1536. [Abstract] [Full Text] [PDF]

				A. G. Rivenbark and W. B. Coleman The Use of Epigenetic Biomarkers for Preclinical Detection of Hepatocellular Carcinoma: Potential for Noninvasive Screening of High-Risk Populations Clin. Cancer Res., April 15, 2007; 13(8): 2309 - 2312. [Full Text] [PDF]