By Will Boggs MD
NEW YORK (Reuters Health) – A single nucleotide polymorphism (SNP) in the tolloid-like 1 (TLL1) gene is associated with the development of hepatocellular carcinoma (HCC) after eradication of hepatitis C virus (HCV) infection, researchers from Japan report.
“When we constructed different models for predicting HCC in patients with mild as opposed to advanced hepatic fibrosis by combining this TLL1 variant with other distinct risk factors, these proposed models including TLL1 variant could be useful for predicting the occurrence of HCC after achieving sustained virological response (SVR) in the clinical practice,” Dr. Yasuhito Tanaka from Nagoya City University Graduate School of Medical Sciences told Reuters Health by email.
Even after SVR, as many as 2% of patients develop HCC within three years and as many as 8.8% develop HCC within five years, Dr. Tanaka and colleagues write in Gastroenterology, online February 3.
The team conducted a genome-wide association study (GWAS) in Japanese patients to identify genetic variants associated with HCC occurrence after eradication of HCV by interferon-based therapy.
The SNP rs17047200, located within the intron of TLL1 on chromosome 4, had the strongest association with the development of HCC after HCV eradication.
There were no SNPs in strong linkage disequilibrium with rs17047200 and none more promising in the exon or promoter regions of TLL1.
“Interestingly, these results were quite different from those of HCV-related HCC (where MICA and DEPDC5 are implicated),” Dr. Tanaka said.
On multivariate analysis, rs17047200 AT/TT was associated with a 78% increased risk for developing HCC (p=0.008). In the mild-fibrosis group, older age was also an independent risk factor for developing HCC, and in the advanced fibrosis group, higher post-treatment alpha-fetoprotein (AFP) and lower albumin level were additional risk factors.
In two rat models of hepatic fibrosis, levels of mRNA were TLL1 were increased, but in only one model did TLL1 mRNA levels parallel the progression of hepatic fibrosis. In chronic hepatitis C patients, TLL1 mRNA levels also increased in parallel with the progression of hepatic fibrosis.
“These data firstly showed the relationship between TLL1/Tll1 expression and hepatic stellate cell (HSC) activation or hepatic-fibrosis progression using in vitro and in vivo models (NASH-related HCC model) as well as human samples, suggesting that our results might contribute to the elucidation of the new mechanism of hepatic fibrogenesis and carcinogenesis,” Dr. Tanaka explained.
“Tests for the TLL1 SNP might be used to identify patients at risk for HCC after an SVR to treatment of HCV infection,” Dr. Tanaka said. “When physicians combine the result of TLL1 SNP with other distinct risk factors, such as the elder age, fibrosis stage, and high AFP, the prediction of HCC occurrence after achieving SVR could be improved in the clinical practice.”
“Interferon (IFN)-free oral treatment regimens combining direct-acting antivirals are becoming the standard of care for anti-HCV therapy in developed countries,” he added. “Future studies are necessary to evaluate whether the TLL1 variant is associated with HCC development after achieving SVR following IFN-free therapy.”
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