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Gene Expression Profiling Reveals Potential Biomarkers of Human Hepatocellular Carcinoma

Authors' Affiliations: ¹ Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute; ² Laboratory of Cancer Genetics, National Human Genome Research Institute, Bethesda, Maryland; ³ Liver Cancer Institute and Zhongshan Hospital, Fudan University and ⁴ Shanghai Public Health Center, Shanghai, China

Requests for reprints: Xin Wei Wang, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, 37 Convent Drive, MSC 4258, Building 37, Room 3044A, Bethesda, MD 20892-4258. Phone: 301-496-2099; Fax: 301-496-0497; E-mail: xw3u{at}nih.gov or Zhao-You Tang, Liver Cancer Institute of Fudan University, Shanghai, China. E-mail: ytang8{at}yahoo.com.cn.

Purpose: Hepatocellular carcinoma (HCC), a common cancer worldwide, has a dismal outcome partly due to the poor identification of early-stage HCC. Currently, one third of HCC patients present with low serum -fetoprotein (AFP) levels, the only clinically available diagnostic marker for HCC. The aim of this study was to identify new diagnostic molecular markers for HCC, especially for individuals with low serum AFP.

Experimental Design: We used the microarray technique to determine the expression profiles of 218 HCC specimens from patients with either high or low serum AFP. From the microarray study, we selected five candidate genes (i.e., GPC3, PEG10, MDK, SERPINI1, and QP-C), which were overexpressed in HCCs. Using quantitative real-time PCR analyses, we validated the expression of these five genes in 50 AFP-normal and 8 AFP-positive HCC specimens and 36 cirrhotic noncancerous hepatic specimens, which include 52 independent specimens not used in microarray analysis.

Results: A significant increase in the expression of the five candidate genes could be detected in most of the HCC samples, including those with normal serum AFP and small tumors. GPC3, MDK, and SERPINI1 encode known serum proteins. Consistently, a significant increase in serum midkine, encoded by MDK, was associated with HCC patients, including those with normal serum AFP. Using prediction analysis of microarray, we showed that a combined score of these five genes can accurately classify noncancerous hepatic tissues (100%) and HCC (71%).

Conclusions: We suggest that a diagnostic signature approach using a combined score of these five biomarkers rather than a single marker may improve the prediction accuracy of HCC patients, including those with normal serum AFP and smaller-sized tumors.