Gene Expression Profiling Reveals Potential Biomarkers of Human Hepatocellular Carcinoma

Abstract

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 a-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.Hepatocellular carcinoma (HCC), endemic to Asia and Africa with a rising incidence in Western countries (1 -3), is one of the most common and aggressive cancers worldwide. It has been the third cancer killer worldwide and the second cancer killer in China since 1990s (4, 5). Globally, the 5-year survival rate of HCC is <5% and f598,000 HCC patients die each year (6). The high mortality associated with this disease is mainly attributed to the inability to diagnose HCC patients at an early stage. In fact, most symptomatic HCC patients are diagnosed at an advanced stage, thus precluding their chance for surgical intervention (7). In contrast, HCC patients who were diagnosed at an early stage and received curative resection had a significantly improved survival time (8 -10). Thus, early detection and resection have been generally recognized as the most important factors to achieve long-term survival for HCC patients.Since its detection in the serum of HCC patients in 1970s, afetoprotein (AFP) has been the only serologic marker widely used for diagnosing HCC patients. This marker allows the identification of a small set of HCC patients with smaller tumors, and these patients have a relatively long-term survival rate following curative treatment (8 -10). Presently,...

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