BOSTON — A gene signature that predicts survival after surgery for hepatocellular carcinoma also predicts the outcome of liver cirrhosis, a study has shown.
“The findings suggest that we might be able to identify patients who need preventive treatment for advanced cirrhosis and possibly hepatocellular carcinoma,” Dr. Yujin Hoshida said at the annual meeting of the American Association for the Study of Liver Diseases.
Compensated cirrhotic patients at risk of poor prognosis can be identified via the 186-gene signature of nontumor liver tissue, Dr. Hoshida said.
The investigators performed whole-genome gene expression analysis of liver biopsy specimens obtained from 276 patients with compensated cirrhosis who were included in a prospective surveillance study for hepatocellular carcinoma, said Dr. Hoshida of the Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge.
Dr. Hoshida and his colleagues previously developed and reported (N. Engl. J. Med. 2008;359:1995–2004) a technique for globally profiling gene expression from formalin-fixed, paraffin-embedded (FFPE) tissues. The method enabled them to profile both nontumor and cancerous tissue obtained from 307 liver cancer patients participating in prospective surveillance studies.
The technique involved the use of a modified cDNA-mediated annealing, selection, extension, and ligation assay to interrogate approximately 6,000 genes expressed in the tumor and nontumor tissue. By partitioning samples into training and validation sets, the investigators were able to develop a 186-gene signature of nontumor tissues to predict hepatocellular carcinoma survival.
In the current study, the investigators used Cox regression modeling to evaluate the potential associations between the 186-gene signature and overall survival, hepatocellular carcinoma, and hepatic decompensation in patients with compensated cirrhosis.
Almost all (98%, or 270) of the 276 patients from whom biopsy specimens were obtained were classified as Child-Pugh A with respect to cirrhosis severity, Dr. Hoshida said. Approximately 90% of the participants had hepatitis C infection, and the median baseline serum alpha-fetoprotein level was 6 mg/dL. Most patients (62%) were male.
During the prospective surveillance period (median follow-up of 9.8 years), 90 patients (33%) died, 81 (29%) developed hepatocellular carcinoma, and 88 (32%) developed hepatic decompensation, he reported.
In multivariate analyses, the 186-gene signature was associated with overall survival, with a hazard ratio (HR) of 2.2. It also was associated with hepatocellular carcinoma development (HR, 1.6) and hepatic decompensation (HR, 2.1). The association between the gene signature and each of the three outcomes remained significant after adjustment for bilirubin greater than 1.0 mg/dL and platelet count, Dr. Hoshida said.
Subsequent gene set enrichment analysis revealed enrichment of metabolic related pathways in patients with a good prognosis and enrichment of pathways associated with inflammation (including those related to interferon and tumor necrosis factor-alpha signaling) in patients with a poorer prognosis, he noted.
Dr. Hoshida reported having no conflicts of interest.