Hepatocellular carcinoma in patients infected with different hepatitis C genotypes

Nn, Zein; Poterucha, JJ; Rh, Wiesner; Jb, Gross; Gossard, A.C.; Wendt, N.; Mitchell, P. Shawn; Germer, JJ; Persing, DH

doi:10.1016/0016-5085(95)29129-6

Cited by 26 publications

(40 citation statements)

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“…To clarify whether or not aa position 91 is important to promote MSI, further analysis using chimeric core proteins will be necessary. On the other hand, several studies have described an increased risk of HCC in patients infected with HCV genotype 1b (51,52), although the contradictory result has also been reported (53). The fact that the core protein belonging to genotype 1b was most effective at promoting the MSI in hepatocyte cells may be related to the increased risk of HCC in patients infected with HCV genotype 1b.…”

Section: Discussionmentioning

confidence: 99%

Promotion of Microsatellite Instability by Hepatitis C Virus Core Protein in Human Non-neoplastic Hepatocyte Cells

et al. 2004

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Hepatitis C virus proteins exert an effect on a variety of cellular functions, including gene expression, signal transduction, and apoptosis, and because they possess oncogenic potentials, they have also been suggested to play an important role in hepatocarcinogenesis. Although the mechanisms of hepatocarcinogenesis remain poorly understood, we hypothesized that the disease may arise because of a disturbance of the DNA repair system by hepatitis C virus proteins. To test this hypothesis, we developed a reproducible microsatellite instability assay system for mismatch-repair using human-cultured cells transducted with pCXpur retrovirus expression vector, in which the puromycin resistance gene was rendered out-of-frame by insertion of a (CA) 17 dinucleotide repeat tract immediately following the ATG start codon. Using several human cancer cell lines known to be replication error positive or negative, we demonstrated that this assay system was useful for monitoring the propensity for mismatch-repair in the cells. This assay system was applicable to nonneoplastic human PH5CH8 hepatocytes, which could support hepatitis C virus replication. Using PH5CH8 cells, in which hepatitis C virus proteins were stably expressed by the retrovirus-mediated gene transfer, we found that the core protein promoted microsatellite instability in PH5CH8 cells. Interestingly, such promotion by the core protein only occurred in cells having the core protein belonging to genotype 1b or 2a and did not occur in cells having the core protein belonging to genotype 1a, 2b, or 3a. This is the first report to demonstrate that the core protein may disturb the DNA repair system.

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Section: Discussionmentioning

confidence: 99%

Promotion of Microsatellite Instability by Hepatitis C Virus Core Protein in Human Non-neoplastic Hepatocyte Cells

et al. 2004

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“…In general, HCV type 2 and 3 isolates have higher rates of response to therapy than type 1 isolates. In addition, some studies suggest that genotype alone may predict disease severity; e.g., patients infected with HCV genotype 1a or 1b may exhibit more severe liver disease (4,6,18,(27)(28)(29)(30)(31)(42)(43)(44). These findings indicate an important role of genotype identification for prediction of the outcome of HCV infection and the selection of patients for treatment protocols.…”

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confidence: 99%

Hepatitis C Virus Genotyping: Interrogation of the 5′ Untranslated Region Cannot Accurately Distinguish Genotypes 1a and 1b

2002

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Although the 5 untranslated region (5 UTR) is the most conserved region of the hepatitis C virus (HCV) genome, it has been suggested that interrogation of this region is sufficient for determination of the HCV genotype. We compared two methods of determination of the HCV genotype: (i) direct sequencing of the DNA of the NS-5b region and (ii) reverse line probe assay (LiPA; INNO-LiPA HCV II; Innogenetics N.V.) of the 5 UTR. There was 100% concordance between the two methods for genotype but only 80% concordance for subtype. A significant percentage of genotype 1a isolates were misclassified by LiPA as genotype 1b. Sequence analysis revealed that the only consistent difference in the 5 UTR for these genotype 1a isolates misclassified as genotype 1b was a single nucleotide (A/G) at position ؊99 of the HCV genome. All isolates with discordant results analyzed had a G at this position, consistent with LiPA determination of these samples as subtype 1b. However, sequence analysis of 222 nucleotides in the NS-5b region clearly identified all of these isolates as subtype 1a. Population distribution data from the University of Pittsburgh Medical Center of over 200 samples analyzed by sequencing of the NS-5b region and over 1,000 samples analyzed by LiPA also indicated that INNO-LiPA HCV II cannot accurately differentiate HCV genotype 1a isolates from HCV genotype 1b isolates. We provide evidence that the A/G at position ؊99 represents a sequence polymorphism in the HCV genome that cannot differentiate subtype 1a from subtype 1b isolates. In conclusion, the 5 UTR is not heterogeneous enough for use in determination of the HCV subtype and cannot be used for differentiation of HCV genotypes 1a and 1b.Hepatitis C virus (HCV) is an enveloped positive singlestranded RNA virus which is the major cause of chronic hepatitis worldwide (2, 12). Chronic hepatitis resulting from HCV infection may lead to severe sequelae, including hepatic cirrhosis and hepatocellular carcinoma (3). HCV demonstrates a high degree of sequence variation throughout its genome and exists in vivo as a group of heterogeneous but closely related quasispecies (8,20). However, the levels of heterogeneity differ considerably among the various regions of the virus, ranging from as little as 10% in the 5Ј untranslated region (5Ј UTR) to 50% or more within the E1 region (8,10,32). Based on the analysis of variable coding regions in the viral genome, distinct genotypes as well as subtypes have been defined (10,16,34). The distribution of HCV genotypes differs geographically, with subtype 1a being most common in the United States, subtype 1b being most common in Europe and Japan, and other genotypes being prevalent in other parts of the world (for a review, see reference 41). Several studies have shown that HCV genotype influences the response to therapy with alpha interferon alone or in combination with ribavirin (1,14,23,43). In general, HCV type 2 and 3 isolates have higher rates of response to therapy than type 1 isolates. In addition, some studies suggest that g...

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“…Amoroso et al (1) found that the rate of progression to chronic infection after acute exposure to HCV was 92% among patients who were infected with genotype 1b, whereas that rate was 33 to 50% among those infected with strains of other genotypes. Zein et al (37,39) found that genotype 1b strains occurred significantly more frequently among patients with cirrhosis and those patients requiring liver transplantation. Patients infected with genotype 1b and possibly genotype 1a may have a more unfavorable response to treatment with interferon than those infected with genotypes 2 or 3 (38).…”

Section: Discussionmentioning

confidence: 99%

“…Clinical strains exhibit a great degree of genetic heterogeneity, and it is thought that such strain differences influence the clinical outcome after infection as well as transmission patterns among susceptible hosts (1,32,37,40). Hence, genotypic characterization of HCV has become an important part of clinical management and public health control of hepatitis C. At the 2nd International Conference of HCV and Related Viruses, a consensus classification scheme was proposed for HCV.…”

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confidence: 99%

“…Several studies have shown that genotype 1, especially subtype 1b, is associated with a less favorable outcome after interferon treatment (7,10,15,21,22,26,35,38,40). There is also evidence that subtype 1b is associated with an increased risk for the development of severe sequelae such as liver cirrhosis and hepatocellular carcinoma (19,37). However, other studies do not show this association (2,13,32).…”

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confidence: 99%

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Nested Restriction Site-Specific PCR To Detect and Type Hepatitis C Virus (HCV): a Rapid Method To Distinguish HCV Subtype 1b from Other Genotypes

et al. 2001

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Genotypic differentiation of hepatitis C virus (HCV) has become an integral part of clinical management and epidemiologic studies of hepatitis C infections. Thus, it is extremely important in areas such as the Czech Republic, where current instrumentation and kits for assessing HCV infection are too costly for widespread use. We describe a new and relatively inexpensive method called nested restriction site-specific PCR (RSS-PCR) that generates a "fingerprint" pattern to represent an HCV genotype without the use of restriction endonucleases and that specifically differentiates HCV genotype 1b from the other HCV genotypes. The RSS-PCR method was applied directly to serum samples from patients with hepatitis C from the Czech Republic and from patients with known HCV genotypes from the United States. The method was validated by comparison of the subtype determined by RSS-PCR to the subtype determined from analysis of the 5 noncoding region (NC) or the nonstructural protein gene (NS5b) nucleotide sequence of HCV in these clinical samples. From 75 Czech samples containing HCV RNA, three distinct RSS-PCR patterns were observed; 54 were predicted to contain subtype 1b, 19 were predicted to contain subtype 1a, and 2 were predicted to contain subtype 3a. Among 54 samples predicted to contain HCV genotype 1b, all were confirmed by their 5 NC or NS5b sequences to be subtype 1b. Thus, both the sensitivity and specificity of the RSS-PCR test for the differentiation of HCV subtype 1b from the others were 100%. While the assay described here was designed to specifically differentiate HCV subtype 1b from the other HCV genotypes, the RSS-PCR method can be modified to differentiate any HCV genotype or subtype of interest. Its simplicity and speed may provide new opportunities to study the epidemiology of HCV infections and the relationship between HCV genotypes and clinical outcome by more laboratories throughout the world.

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Hepatocellular carcinoma in patients infected with different hepatitis C genotypes

Cited by 26 publications

References 0 publications

Promotion of Microsatellite Instability by Hepatitis C Virus Core Protein in Human Non-neoplastic Hepatocyte Cells

Promotion of Microsatellite Instability by Hepatitis C Virus Core Protein in Human Non-neoplastic Hepatocyte Cells

Hepatitis C Virus Genotyping: Interrogation of the 5′ Untranslated Region Cannot Accurately Distinguish Genotypes 1a and 1b

Nested Restriction Site-Specific PCR To Detect and Type Hepatitis C Virus (HCV): a Rapid Method To Distinguish HCV Subtype 1b from Other Genotypes

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