Abstract
4106 Background: Some 20-30% of patients with chronic hepatitis B (CHB) eventually develop hepatocellular carcinoma (HCC), a disease with poor prognosis and high mortality unless detected early. Ultrasound and/or alpha-fetoprotein (AFP) are widely used for HCC surveillance. However these technologies are operator-dependent, have low sensitivity and are considered inadequate for screening. This study describes a blood-based gene-expression signature prognostic for HCC in CHB patients. Methods: PaxGene was used to extract RNA from whole blood samples taken from more than 1,000 Malaysian patients (matched HCC, CHB, healthy controls). Complementary DNA was generated from isolated RNA via reverse transcription and analyzed using Affymetrix U133Plus 2.0 with MAS 5.0 normalization. To minimize bias we developed a novel algorithm based on SentinelPair regression analysis to identify biomarker panels. A Monte Carlo search identified pair combinations that could differentiate between cancer and controls. Twelve genes were selected for qRT-PCR Cohort 1 verification (n=139). Six genes were then short-listed for qRT-PCR Cohort 2 verification using independent samples (n=150). Results: Multivariate quantitative microarray analysis of 147 samples (HCC=47; CHB=50; controls=50) identified 12 probe sets differentially expressed between HCC patients and controls and CHB (ROC AUC=0.90). These genes were evaluated using qRT-PCR on the same cohort (ROC AUC=0.86). Six genes were subsequently short listed for qRT-PCR Cohort 2 verification. The AUC of the 6-gene-combination of Cohort 2 (HCC=50; CHB=50; controls=50) was 0.80. Importantly, of the thirteen HCC with low AFP (<15ng/ml), 9 were predicted as “positive.” Conclusions: Blood RNA biomarkers identified in this study may form the basis of a test that can be used in patients with CHB for detection of early HCC, potentially improving prognosis for this cancer. This blood-based test would represent a significant clinical alternative to ultrasound and/or AFP.
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