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TLL1 variant may predict HCC development after HCV eradication

Jairia Dela Cruz
15 May 2017

A genetic variant in the tolloid like 1 (TLL1) gene is strongly associated with the development of hepatocellular carcinoma (HCC) after the eradication of hepatitis C virus (HCV) infection by interferon-based therapy, according to a genome-wide association (GWAS) study.

Using genomic DNA data from 457 HCV patients who had achieved sustained virologic response (SVR) with treatment, researchers found that the variant rs17047200—located within the intron of TLL1 on chromosome 4—was involved in hepatocarcinogenesis (odds ratio [OR], 2.35; 95 percent CI, 1.48 to 3.75; p=2.33×10−4 in the allele frequency model). The result was replicated in an independent cohort of 486 patients. [Gastroenterology 2017;152:1383–1394]

Of note, “there was a genome-wide level of significance when the results of the GWAS and replication study were combined (OR, 2.37; 1.74 to 3.23; p=2.66×10−8),” they said.

Further analysis using stepwise Cox proportional hazard modelling showed rs17047200 AT/TT to be an independent risk factor for HCC (hazard ratio, 1.78; 1.17 to 2.70; p=0.008). The TLL1 variant strongly predicted cancer development even in patients with mild hepatic fibrosis. Other HCC risk factors included male sex, older age, lower albumin level, advanced hepatic fibrosis stage, presence of diabetes and higher post-treatment α-fetoprotein level.

“Mammalian TLL1 is one of the four members of the bone morphogenetic protein 1/tolloid (BMP1/TLD)-like proteinase family. Bioinformatic analysis on protein−protein interaction networks indicated that the TLL1 and BMP1 exert several biological roles in regulating extracellular matrix assembly and in transforming growth factor (TGF)−β signalling,” researchers said.

“Chronic liver pathologies, including HCV infection, result in up-regulation of TGF-β signalling and subsequently activate human hepatic stellate cells (HSCs), causing excessive accumulation of the various extracellular matrix proteins in the liver,” they added.

Indeed, when the researchers investigated the gene expression of TLL1 and BMP1 using human samples and in vitro and in vivo models, levels of TLL1 messenger RNA (mRNA) in HSCs increased on activation. The levels also increased in liver tissues of patients with progression of fibrosis and of rodents with hepatic fibrogenesis. Patients with rs17047200 AT/TT showed higher gene expression levels of TLL1 short variants, including isoform 2. On the other hand, BMP1 levels remained similar.

“Interestingly, these results indicated that TLL1 would specifically play a role in hepatic fibrogenesis, although previous studies had shown that TLL1 and BMP1 are co-expressed in various tissues,” researchers said.

“Although the molecular mechanisms of hepatocarcinogenesis have not been fully elucidated, the cirrhotic tissue microenvironment is thought to cause initiation and promotion of neoplastic clones by facilitating genetic aberrations and cellular transformation, resulting in HCC development,” they added.

Taking into consideration data from available evidence, researchers hypothesized that TLL1 could contribute to HCC development mainly through cirrhosis-driven carcinogenesis and probably via pro-oncogenic roles.

“Therefore, genetic testing of the TLL1 variant would be useful for implementing personalized surveillance of HCC in patients who have achieved SVR. Additionally, our results might contribute to the elucidation of the mechanism of hepatic fibrogenesis and carcinogenesis,” they said.

The study was limited by a small sample size, homogenous patient population (all patients were Japanese were included), as genotype and allele frequencies at rs17047200 are different among ethnicities. Additionally, the current retrospective case-control study used the original inclusion criteria of patients derived from an exploratory study.

Continued surveillance for HCC still recommended

Experts wrote in an accompanying editorial that the results of the present study provide important new insights that will stimulate research into the role of TLL1 in liver fibrogenic and oncogenic pathways. [Gastroenterology 2017;152:1282–1284]

“As for all GWAS, these results will need to be independently validated. The cohort used was notable for Japanese ethnicity, older age, high prevalence of genotypes 1 and 2, and high frequency of HCC in people with mild to moderate liver fibrosis. People with decompensated liver disease were excluded, a group at very high risk for HCC. Replication cohorts in Western populations will be important,” said Drs Jessica Howell and Alexander Thompson from the St. Vincent’s Hospital Melbourne in Australia.

“Furthermore, the treatment paradigm for HCV has shifted dramatically. IFN is no longer the backbone of antiviral therapy, and highly effective, all-oral direct-acting antiviral regimens (DAAs) are now the standard of care. IFN is known to have antitumour activity, and it is not known whether this, independent of antiviral activity, contributed to the protective benefit against HCC observed in IFN responders,” they continued.

They pointed out that while TLL1 genotyping has the potential to improve risk stratification for HCC post-SVR, the data presented cannot yet be used to identify low-risk individuals who no longer require HCC surveillance.

“Until such data become available, we recommend continuing surveillance for HCC in all people with cirrhosis after SVR,” they said.

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Most Read Articles
29 Nov 2017
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Christina Lau, 22 Oct 2015
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Cathy Chow, PhD, 27 Aug 2015

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