Review
A concise review of serum markers for hepatocellular cancer

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Abstract

Background: The rising incidence of hepatocellular cancer in the US and worldwide has sparked a renewed interest in HCC serum markers. HCC typically develops in patients with chronic liver disease and cirrhosis. It is in these target populations that serum markers are most urgently needed. Unfortunately, the currently available markers lack sensitivity and specificity. A number of novel candidate markers have recently been introduced. Methods: We performed a review of the literature (2001–2006) of traditional and novel serum markers for hepatocellular cancer. Results: Several promising new HCC markers have been identified over the past 5 years. They include single proteins, complex proteomics features, and tumor-specific autoantibodies. The excitement about the new markers is tempered by the realization that none of them have yet met the most stringent criteria defined by the Early Detection Research Network (EDRN). Conclusion: A new generation of HCC serum markers awaits validation in properly controlled clinical studies.

Section snippets

Review criteria

We performed a MEDLINE search of the PubMed database by combining the keywords ‘hepatocellular cancer’ and ‘serum marker’ for all journals published in the English language from 2001 to 2006. The search was limited to ‘human subjects’. Studies based on measurements of messenger RNAs, DNA or DNA polymorphisms, lipids, or bile acids as markers were excluded. Anecdotal reports, uncontrolled studies, or studies in which the sensitivity or specificity of a given marker was not provided were

α-Fetoprotein

Alpha-fetoprotein (AFP) is an oncofetal glycoprotein of unknown function that is present at increased levels in sera of patients with cirrhosis and HCC. AFP was discovered by Abelev et al. [6]. The first quantitative serum assays for AFP were established by Ruoshlati and Seppala [7], and their performance has been extensively evaluated. The sensitivity and specificity of AFP in HCC screening and surveillance studies varies according to test thresholds, study designs, and patient populations

Squamous cell carcinoma antigen

Squamous cell carcinoma antigen (SCCA) is a serine protease inhibitor (serpin) that is expressed in many normal squamous epithelial cells [73]. Increased SCCA levels have been found in head and neck cancer tissues and other epithelial cancers [74].

Gianelli and colleagues performed ELISA measurements of serum SCCA in patients with HCC (n = 120), cirrhosis (n = 90), and healthy subjects (n = 41) [75] (Xeptagen, Naples, Italy). SCCA levels were significantly increased in HCC patients as compared to

Serum proteomics

Serum proteomics studies were traditionally based on two-dimensional gel electrophoresis, although this method is insufficiently sensitive to detect low-abundance proteins [76]. Steel and co-workers performed 2-dimensional gel electrophoresis on sera from HBV-infected patients with and without HCC. Two protein signals – corresponding to C3 complement and apolipoprotein A1, respectively – were consistently less abundant in HCC patients as compared to HBV-negative controls and HBV-carriers [77].

HCC-specific auto-antibodies

An extensive body of literature has documented the presence of tumor-derived autoantibodies (TAA) in the sera of HCC patients. They include some of the earliest TAAs, such as anti-p53 [95], as well as new members (such as anti-telomerase [96]). TAAs may be markers of the malignant transformation since their occurrence appears to be triggered by the abnormal processing of antigenic cellular proteins during carcinogenesis [97], [98].

A common feature of HCC-TAAs is their low sensitivity—they are

Conclusion and outlook

The HCC serum marker field is primed for a new generation of candidate markers that have the potential to replace its flawed leader AFP (Table 2). Novel approaches involving serum proteomics and autoantibody discovery should result in the identification of new candidates in the near future. The strict application of the EDRN criteria will aid in the assessment of their diagnostic utility, and provide an objective basis for the assessment of their clinical utility.

Conflict of interest

None declared.

Acknowledgement

This study was supported by a VA Merit Review to C.J.F.

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