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An interferon response gene signature is associated with the therapeutic response of hepatitis C patients.

Pfeffer LM, Li K, Fleckenstein JF, Marion TN, Diament J, Yang CH, Pfeffer SR, Fan M, Handorf E, Handorf CR - PLoS ONE (2014)

Bottom Line: Therefore, it is critical to understand the basic mechanisms that underlie the therapeutic resistance to IFN action in HCV-infected individuals, and there is an urgent need to identify those patients most likely to respond to IFN therapy for HCV.Based on these findings, a statistical model was developed to help predict the response of patients to IFN therapy, and compared to results obtained to the IL28 mutation model, which is highly predictive of the response to IFN-based therapy in HCV-infected patients.We found that a model incorporating gene expression data can improve predictions of IFN responsiveness compared to IL28 mutation status alone.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.

ABSTRACT
Infection with the hepatitis C virus (HCV) is a major cause of chronic liver diseases and hepatocellular carcinoma worldwide, and thus represents a significant public health problem. The type I interferon (IFN), IFNα, has been successful in treating HCV-infected patients, but current IFN-based treatment regimens for HCV have suboptimal efficacy, and relatively little is known about why IFN therapy eliminates the virus in some patients but not in others. Therefore, it is critical to understand the basic mechanisms that underlie the therapeutic resistance to IFN action in HCV-infected individuals, and there is an urgent need to identify those patients most likely to respond to IFN therapy for HCV. To characterize the response of HCV-infected patients to treatment with IFNα, the expression of an IFN-response gene signature comprised of IFN-stimulated genes and genes that play an important role in the innate immune response was examined in liver biopsies from HCV-infected patients enrolled in a clinical trial. In the present study we found that the expression of a subset of IFN-response genes was dysregulated in liver biopsy samples from nonresponsive hepatitis C patients as compared with virologic responders. Based on these findings, a statistical model was developed to help predict the response of patients to IFN therapy, and compared to results obtained to the IL28 mutation model, which is highly predictive of the response to IFN-based therapy in HCV-infected patients. We found that a model incorporating gene expression data can improve predictions of IFN responsiveness compared to IL28 mutation status alone.

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Differential expression of an IFN-regulated signature geneset in responders versus nonresponders to therapy.Expression of an IFN-regulated signature geneset was determined in RNA extracted from FFPE liver biopsies by nCounter analysis. Boxplots of genes found to be statistically differentially expressed by nonparametric Mann-Whitney analysis (p<0.05).
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pone-0104202-g001: Differential expression of an IFN-regulated signature geneset in responders versus nonresponders to therapy.Expression of an IFN-regulated signature geneset was determined in RNA extracted from FFPE liver biopsies by nCounter analysis. Boxplots of genes found to be statistically differentially expressed by nonparametric Mann-Whitney analysis (p<0.05).

Mentions: In the 130 liver samples subjected to Nanostring analysis, 43 were obtained from HCV-infected patients who responded to IFN-ribavirin therapy (responders), 56 from HCV-infected patients who did not respond to therapy (nonresponders), and 31 from patients who had an initial virological response to therapy, but then relapsed during therapy and had high viral HCV titers (relapsers). Of these 130 patient samples, 112 had their IL28B genotype determined (Table 3). The liver tissue was obtained from 80 African-American (AA) and 50 Caucasian hepatitis C-infected patients (Table 4). Consistent with the previous findings that African Americans demonstrate a lower response rate to IFN than Caucasians, in the African American group of patients 27.5% were classified as responders, 57.5% as non-responders and 15% as relapsers. In contrast, in the Caucasian group of patients 50% were classified as responders, 22.1% as non-responders and 27.9% as relapsers. Initial analysis of differences in gene expression between responders and non-responders (excluding relapsers) revealed statistically significant differences (p<0.05) in the expression of 16 out of the 39 genes examined, which included CCL5, DDX58/RIG-I, DHX58/LGP2, EIF2AK2, IFI6, IFI16, IFIH1/MDA5, IRF7, ISG20, MX1, OAS1, PLSCR1, RSAD2, STAT1, TLR3 and XAF1 (Figure 1). Most interestingly, these genes were expressed at higher levels in liver biopsies from patients that did not respond to IFN-ribavirin therapy as compared to the responders to therapy. The higher expression levels of ISGs prior to therapy in nonresponders compared with responders was consistent with several previous reports [27]–[30]. It is important to note that there was no relationship found between the expression of the IFNβ gene in liver biopsies, and responsiveness to exogenous IFN therapy. This finding is consistent with our previous report that serum levels of type I IFNs in patients chronically infected with HCV did not correlate with the response to exogenous IFN therapy [22].


An interferon response gene signature is associated with the therapeutic response of hepatitis C patients.

Pfeffer LM, Li K, Fleckenstein JF, Marion TN, Diament J, Yang CH, Pfeffer SR, Fan M, Handorf E, Handorf CR - PLoS ONE (2014)

Differential expression of an IFN-regulated signature geneset in responders versus nonresponders to therapy.Expression of an IFN-regulated signature geneset was determined in RNA extracted from FFPE liver biopsies by nCounter analysis. Boxplots of genes found to be statistically differentially expressed by nonparametric Mann-Whitney analysis (p<0.05).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4128657&req=5

pone-0104202-g001: Differential expression of an IFN-regulated signature geneset in responders versus nonresponders to therapy.Expression of an IFN-regulated signature geneset was determined in RNA extracted from FFPE liver biopsies by nCounter analysis. Boxplots of genes found to be statistically differentially expressed by nonparametric Mann-Whitney analysis (p<0.05).
Mentions: In the 130 liver samples subjected to Nanostring analysis, 43 were obtained from HCV-infected patients who responded to IFN-ribavirin therapy (responders), 56 from HCV-infected patients who did not respond to therapy (nonresponders), and 31 from patients who had an initial virological response to therapy, but then relapsed during therapy and had high viral HCV titers (relapsers). Of these 130 patient samples, 112 had their IL28B genotype determined (Table 3). The liver tissue was obtained from 80 African-American (AA) and 50 Caucasian hepatitis C-infected patients (Table 4). Consistent with the previous findings that African Americans demonstrate a lower response rate to IFN than Caucasians, in the African American group of patients 27.5% were classified as responders, 57.5% as non-responders and 15% as relapsers. In contrast, in the Caucasian group of patients 50% were classified as responders, 22.1% as non-responders and 27.9% as relapsers. Initial analysis of differences in gene expression between responders and non-responders (excluding relapsers) revealed statistically significant differences (p<0.05) in the expression of 16 out of the 39 genes examined, which included CCL5, DDX58/RIG-I, DHX58/LGP2, EIF2AK2, IFI6, IFI16, IFIH1/MDA5, IRF7, ISG20, MX1, OAS1, PLSCR1, RSAD2, STAT1, TLR3 and XAF1 (Figure 1). Most interestingly, these genes were expressed at higher levels in liver biopsies from patients that did not respond to IFN-ribavirin therapy as compared to the responders to therapy. The higher expression levels of ISGs prior to therapy in nonresponders compared with responders was consistent with several previous reports [27]–[30]. It is important to note that there was no relationship found between the expression of the IFNβ gene in liver biopsies, and responsiveness to exogenous IFN therapy. This finding is consistent with our previous report that serum levels of type I IFNs in patients chronically infected with HCV did not correlate with the response to exogenous IFN therapy [22].

Bottom Line: Therefore, it is critical to understand the basic mechanisms that underlie the therapeutic resistance to IFN action in HCV-infected individuals, and there is an urgent need to identify those patients most likely to respond to IFN therapy for HCV.Based on these findings, a statistical model was developed to help predict the response of patients to IFN therapy, and compared to results obtained to the IL28 mutation model, which is highly predictive of the response to IFN-based therapy in HCV-infected patients.We found that a model incorporating gene expression data can improve predictions of IFN responsiveness compared to IL28 mutation status alone.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.

ABSTRACT
Infection with the hepatitis C virus (HCV) is a major cause of chronic liver diseases and hepatocellular carcinoma worldwide, and thus represents a significant public health problem. The type I interferon (IFN), IFNα, has been successful in treating HCV-infected patients, but current IFN-based treatment regimens for HCV have suboptimal efficacy, and relatively little is known about why IFN therapy eliminates the virus in some patients but not in others. Therefore, it is critical to understand the basic mechanisms that underlie the therapeutic resistance to IFN action in HCV-infected individuals, and there is an urgent need to identify those patients most likely to respond to IFN therapy for HCV. To characterize the response of HCV-infected patients to treatment with IFNα, the expression of an IFN-response gene signature comprised of IFN-stimulated genes and genes that play an important role in the innate immune response was examined in liver biopsies from HCV-infected patients enrolled in a clinical trial. In the present study we found that the expression of a subset of IFN-response genes was dysregulated in liver biopsy samples from nonresponsive hepatitis C patients as compared with virologic responders. Based on these findings, a statistical model was developed to help predict the response of patients to IFN therapy, and compared to results obtained to the IL28 mutation model, which is highly predictive of the response to IFN-based therapy in HCV-infected patients. We found that a model incorporating gene expression data can improve predictions of IFN responsiveness compared to IL28 mutation status alone.

Show MeSH
Related in: MedlinePlus