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Identifying genes for establishing a multigenic test for hepatocellular carcinoma surveillance in hepatitis C virus-positive cirrhotic patients.

ABSTRACT: In this study, we used the Affymetrix HG-U133A version 2.0 GeneChips to identify genes capable of distinguishing cirrhotic liver tissues with and without hepatocellular carcinoma by modeling the high-dimensional dataset using an L(1) penalized logistic regression model, with error estimated using N-fold cross-validation. Genes identified by gene expression microarray included those that have important links to cancer development and progression, including VAMP2, DPP4, CALR, CACNA1C, and EGR1. In addition, the selected molecular markers in the multigenic gene expression classifier were subsequently validated using reverse transcriptase-real time PCR, and an independently acquired gene expression microarray dataset was downloaded from Gene Expression Omnibus. The multigenetic classifier derived herein did similarly or better than standard abdominal ultrasonography and serum alpha-fetoprotein, which are currently used for hepatocellular carcinoma surveillance. Because early hepatocellular carcinoma diagnosis increases survival by increasing access to therapeutic options, these molecular markers may prove useful for early diagnosis of hepatocellular carcinoma, especially if prospectively validated and translated into gene products that can be reproducibly and reliably tested noninvasively.

SUBMITTER: Archer KJ

PROVIDER: S-EPMC2783293 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionThe risk of hepatocellular carcinoma persists in some patients despite achieving sustained virologic response with current interferon-free direct-acting antiviral therapy for hepatitis C. The subject of an even higher carcinoma risk in this context has been reported and is currently being debated. The quest for understanding this paradox relative to the dynamics of inflammatory biomarkers in cirrhosis patients receiving antiviral therapy thus remains a subject of importance.ObjectiveHere, we aimed at evaluating the effects of direct-acting antiviral therapy-induced hepatitis C cure on plasmatic markers of systemic inflammation measured before, during and after treatment. Specifically, soluble immune mediator phenotype associations that impact the odds of hepatocellular carcinoma development and the related changes that arise upon direct-acting antiviral-mediated hepatitis C clearance in cirrhosis patients was investigated.MethodsEmploying multiplex technology that measured up to 91 circulating biomarker proteins, we profiled the plasma soluble immune mediator concentrations of cirrhosis patients who developed posttreatment hepatocellular carcinoma and their respective negative controls, before and after direct-acting antiviral treatment.ResultsElevated pretherapy concentrations of specific soluble immune mediators including MCP-3, GDNF, CDCP1, IL-17C, IL-17A, signalling lymphocytic activation family 1, CCL11, FGF-5, LIF-R, interleukin 10 (IL-10), IL-10RA, IL-15RA, beta NGF, CCL28, CCL25 and NT-3 distinguished patients who developed posttreatment hepatocellular carcinoma relative to those that did not. Particularly, GDNF, FGF-5 and IL-15RA displayed independent predictive biomarker attributes for delineating carcinoma emergence regardless of de novo or recurrence groupings. Upon successful therapy, the elevated pretherapy soluble immune mediator establishment of the patients who eventually developed hepatocellular carcinoma stayed largely unperturbed whereas a panel of some 38 soluble immune mediators in the posttherapy carcinoma-free patients experienced significant ameliorations.ConclusionsThese results have considerable implications for delineating potential hepatocellular carcinoma emergence before initiating direct-acting antiviral therapy for hepatitis C in cirrhosis patients. They provide preliminary contribution to unravelling cases where the benefit of direct-acting antiviral therapies would be superior to the risk of developing carcinoma.

Project description:BackgroundDespite the recent identification of several prognostic gene signatures, the lack of common genes among experimental cohorts has posed a considerable challenge in uncovering the molecular basis underlying hepatocellular carcinoma (HCC) recurrence for application in clinical purposes. To overcome the limitations of individual gene-based analysis, we applied a pathway-based approach for analysis of HCC recurrence.ResultsBy implementing a permutation-based semi-supervised principal component analysis algorithm using the optimal principal component, we selected sixty-four pathways associated with hepatitis B virus (HBV)-positive HCC recurrence (p < 0.01), from our microarray dataset composed of 142 HBV-positive HCCs. In relation to the public HBV- and public hepatitis C virus (HCV)-positive HCC datasets, we detected 46 (71.9%) and 18 (28.1%) common recurrence-associated pathways, respectively. However, overlap of recurrence-associated genes between datasets was rare, further supporting the utility of the pathway-based approach for recurrence analysis between different HCC datasets. Non-supervised clustering of the 64 recurrence-associated pathways facilitated the classification of HCC patients into high- and low-risk subgroups, based on risk of recurrence (p < 0.0001). The pathways identified were additionally successfully applied to discriminate subgroups depending on recurrence risk within the public HCC datasets. Through multivariate analysis, these recurrence-associated pathways were identified as an independent prognostic factor (p < 0.0001) along with tumor number, tumor size and Edmondson's grade. Moreover, the pathway-based approach had a clinical advantage in terms of discriminating the high-risk subgroup (N = 12) among patients (N = 26) with small HCC (<3 cm).ConclusionsUsing pathway-based analysis, we successfully identified the pathways involved in recurrence of HBV-positive HCC that may be effectively used as prognostic markers.

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Identifying genes for establishing a multigenic test for hepatocellular carcinoma surveillance in hepatitis C virus-positive cirrhotic patients.

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