Identification and Validation of a Novel Gene Signature Associated with the Recurrence of Human Hepatocellular Carcinoma

Abstract

To improve the clinical management of human hepatocellular carcinoma (HCC) by accurate identification, at diagnosis, of patients at risk of recurrence after primary treatment for HCC. Two clinicopathologic variables available at diagnosis, vascular invasion and cirrhosis, together with molecular profiling using Affymetrix human HG-U133A and HG-U133B oligonucleotide probe arrays, were used to identify recurrent HCC disease. HCC patients presented clinically at diagnosis with vascular invasion and cirrhosis showed a high rate (78-83%) of developing recurrent disease within 6 to 35 months. In comparison, most of the HCC patients (80-100%) without vascular invasion and cirrhosis remained disease-free. However, the risk of recurrent disease for HCC patients with either vascular invasion or cirrhosis could not be accurately ascertained. Using a pool of 23 HCC patients with either vascular invasion or cirrhosis as training set, a 57-gene signature was derived and could predict recurrent disease at diagnosis, with 84% (sensitivity 86%, specificity 82%) accuracy, for a totally independent test set of 25 HCC patients with either vascular invasion or cirrhosis. On further analysis, the disease-free rate was significantly different between patients that were predicted to recur or not to recur in the test group (P = 0.002). We have presented data to show that by incorporating the status of vascular invasion and cirrhosis available at diagnosis for patients with HCC after partial curative hepatectomy and a novel 57-member gene signature, we could accurately stratify HCC patients with different risks of recurrence.