BOSTON (FRONTLINE MEDICAL NEWS) – rs4836493, a single nucleotide polymorphism of the gene encoding chondroitin sulfate synthase-3, significantly predicted hepatocellular carcinoma among patients with HCV even when they achieved sustained virologic response on pegylated interferon, according to a genome-wide association study.

The next step is to determine whether rs4836493 predicts liver cancer after SVR on the new direct-acting antiviral regimens, Basile Njei, MD, MPH, said during an oral presentation at the annual meeting of the American Association for the Study of Liver Diseases.

Cirrhotic patients face about a 2%-7% annual risk of hepatocellular carcinoma, noted Dr. Njei of Yale University, New Haven, Conn. “Recent studies show that people with HCV may still develop hepatocellular carcinoma even after achieving SVR,” he said.

To look for genetic predictors of this outcome, he and his associates genotyped 958 patients with HCV and advanced hepatic fibrosis from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study. This trial had evaluated long-term, low-dose pegylated interferon therapy (90 mcg per week for 3.5 years) as a means of keeping fibrosis from progressing among HCV patients who had failed peginterferon and ribavirin therapy.

A total of 63% of patients had cirrhosis, and 55 (5.7%) developed biopsy or imaging-confirmed hepatocellular carcinoma over a median of 80 months of follow-up, Dr. Njei said. After the researchers controlled for age, sex, Ishak fibrosis score, and SVR status, rs4836493 predicted hepatocellular carcinoma with a highly significant P value of .000004.

This SNP is located on the CHSY3 gene, which plays a role in the chondroitin polymerization, tissue development, and morphogenesis, according to Dr. Njei. Notably, the gene has been implicated in the biology of colorectal tumors, he added.

Dr. Njei and his associates genotyped patients by using the 610-Quad platform, which contains more than 600,000 SNPs. They double-checked results and conducted more genetic analyses using PLINK 1.9 , a free, open-source software program for genome-wide association data. Three-quarters of patients in the study were white, 72% were male, and median age at enrollment was 50 years, he noted.

Linking a single SNP to liver cancer despite SVR is a striking finding, but it is also preliminary, Dr. Njei cautioned. “The SNP identified in our discovery genome-wide association study needs future replication and validation in patients who achieve SVR after receiving the new direct-acting antiviral therapies,” he said.

The National Institutes of Health provided partial funding. Dr. Njei and his coinvestigators had no relevant financial conflicts of interest.


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