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 23 May 2018

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Genetic variant associated with liver cancer after HCV eradication

A genome-wide association study reported in May's issue of Gastroenterology identifies TLL1 variant associated with development of hepatocellular carcinoma after eradication of Hepatitis C virus infection.

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There is still a risk for hepatocellular carcinoma development after eradication of hepatitis C virus (HCV) infection with antiviral agents. 

Dr Yasuhito Tanaka and colleagues from Japan investigated genetic factors associated with the development of hepatocellular carcinoma in patients with a sustained virologic response to treatment for chronic HCV infection.

The research team obtained genomic DNA from 457 patients in Japan with a sustained virological response to interferon-based treatment for chronic HCV infection from 2007 through 2015. 

The team conducted a genome-wide association study, followed by a replication analysis of 79 candidate single nucleotide polymorphisms in an independent set of 486 patients in Japan. 

Levels of TLL1 mRNA increased in liver tissues of patients with progression of fibrosis
Gastroenterology
The study end point was hepatocellular carcinoma diagnosis or confirmation of lack of hepatocellular carcinoma. 

The team collected clinical and laboratory data from all patients. 

The researchers analyzed expression levels of candidate gene variants in human hepatic stellate cells, rats with steatohepatitis caused by a choline-deficient L-amino acid-defined diet, and a mouse model of liver injury caused by administration of carbon tetrachloride. 

The team also analyzed expression levels in liver tissues of patients with chronic HCV infection with different stages of fibrosis or tumors vs patients without HCV infection (controls).

The research team found a strong association between the single nucleotide polymorphism rs17047200, located within the intron of the tolloid like 1 gene (TLL1) on chromosome 4, and development of hepatocellular carcinoma.

There was a genome-wide level of significance when the results of the genome-wide association study, and replication study were combined. 

The team showed rs17047200 AT/TT to be an independent risk factor for hepatocellular carcinoma, along with male sex, older age, lower level of albumin, advanced stage of hepatic fibrosis, presence of diabetes, and higher post-treatment level of α-fetoprotein. 

Combining the rs17047200 genotype with other factors, the researchers developed prediction models for hepatocellular carcinoma development in patients with mild or advanced hepatic fibrosis. 

Levels of TII1 messenger RNA (mRNA) in human hepatic stellate cells increased with activation. 

Levels of TLL1 mRNA increased in liver tissues of rodents with hepatic fibrogenesis compared with controls. 

The research team found that levels of TLL1 mRNA increased in liver tissues of patients with progression of fibrosis. 

Gene expression levels of TLL1 short variants, including isoform 2, were higher in patients with rs17047200 AT/TT.

Dr Tanaka's team concludes, "In a genome-wide association study, we identified the association between the single nucleotide polymorphisms rs17047200, within the intron of TLL1, and development of hepatocellular carcinoma in patients who achieved an SVR to treatment for chronic HCV infection."

"We found levels of TII1/TLL1 mRNA to be increased in rodent models of liver injury and liver tissues of patients with fibrosis, compared with controls."

"We propose that this single nucleotide polymorphism might affect splicing of TLL1 mRNA, yielding short variants with high catalytic activity that accelerates hepatic fibrogenesis and carcinogenesis."

"Further studies are needed to determine how rs17047200 affects TLL1 mRNA levels, splicing, and translation, as well as the prevalence of this variant among other patients with hepatocellular carcinoma."

"Tests for the TLL1 single nucleotide polymorphism might be used to identify patients at risk for hepatocellular carcinoma after an sustained virological response to treatment of HCV infection."

Gastroenterol 2017: 152(6): 1383–1394 
01 May 2017

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