Reuters Health Information: Genetic variant linked to risk of liver cancer after hep C eradication
Genetic variant linked to risk of liver cancer after hep C eradication
Last Updated: 2017-02-21
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
�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
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
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