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A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration.

ABSTRACT: The number of patients with HCV-related cirrhosis is increasing, leading to a rising risk of complications and death. Prognostic stratification in patients with early-stage cirrhosis is still challenging. We aimed to develop and validate a clinically useful prognostic index based on genomic and clinical variables to identify patients at high risk of disease progression.We developed a prognostic index, comprised of a 186-gene signature validated in our previous genome-wide profiling study, bilirubin (>1?mg/dL) and platelet count (<100,000/mm(3)), in an Italian HCV cirrhosis cohort (training cohort, n=216, median follow-up 10?years). The gene signature test was implemented using a digital transcript counting (nCounter) assay specifically developed for clinical use and the prognostic index was evaluated using archived specimens from an independent cohort of HCV-related cirrhosis in the USA (validation cohort, n=145, median follow-up 8?years).In the training cohort, the prognostic index was associated with hepatic decompensation (HR=2.71, p=0.003), overall death (HR=6.00, p<0.001), hepatocellular carcinoma (HR=3.31, p=0.001) and progression of Child-Turcotte-Pugh class (HR=6.70, p<0.001). The patients in the validation cohort were stratified into high-risk (16%), intermediate-risk (42%) or low-risk (42%) groups by the prognostic index. The high-risk group had a significantly increased risk of hepatic decompensation (HR=7.36, p<0.001), overall death (HR=3.57, p=0.002), liver-related death (HR=6.49, p<0.001) and all liver-related adverse events (HR=4.98, p<0.001).A genomic and clinical prognostic index readily available for clinical use was successfully validated, warranting further clinical evaluation for prognostic prediction and clinical trial stratification and enrichment for preventive interventions.

SUBMITTER: King LY

PROVIDER: S-EPMC4336233 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Project description:Hepatitis C virus (HCV)-related cirrhosis leads to a heavy global burden of disease. Clinical risk stratification in HCV-related compensated cirrhosis remains a major challenge. Here, we aim to develop a signature comprised of immune-related genes to identify patients at high risk of progression and systematically analyze immune infiltration in HCV-related early-stage cirrhosis patients. Bioinformatics analysis was applied to identify immune-related genes and construct a prognostic signature in microarray data set. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were conducted with the "clusterProfiler" R package. Besides, the single sample gene set enrichment analysis (ssGSEA) was used to quantify immune-related risk term abundance. The nomogram and calibrate were set up via the integration of the risk score and clinicopathological characteristics to assess the effectiveness of the prognostic signature. Finally, three genes were identified and were adopted to build an immune-related prognostic signature for HCV-related cirrhosis patients. The signature was proved to be an independent risk element for HCV-related cirrhosis patients. In addition, according to the time-dependent receiver operating characteristic (ROC) curves, nomogram, and calibration plot, the prognostic model could precisely forecast the survival rate at the first, fifth, and tenth year. Notably, functional enrichment analyses indicated that cytokine activity, chemokine activity, leukocyte migration and chemotaxis, chemokine signaling pathway and viral protein interaction with cytokine and cytokine receptor were involved in HCV-related cirrhosis progression. Moreover, ssGSEA analyses revealed fierce immune-inflammatory response mechanisms in HCV progress. Generally, our work developed a robust prognostic signature that can accurately predict the overall survival, Child-Pugh class progression, hepatic decompensation, and hepatocellular carcinoma (HCC) for HCV-related early-stage cirrhosis patients. Functional enrichment and further immune infiltration analyses systematically elucidated potential immune response mechanisms.

Project description:Gene-expression profiles of hepatitis C-related, early-stage liver cirrhosis Background & Aims: Liver cirrhosis affects 1%M-bM-^HM-^R2% of population and is the major risk factor of hepatocellular carcinoma (HCC). Hepatitis C cirrhosis-related HCC is the most rapidly increasing cause of cancer death in the US. Non-invasive methods have been developed to identify patients with asymptomatic, early-stage cirrhosis, increasing the burden of HCC surveillance, but biomarkers are needed to identify patients with cirrhosis who are most in need of surveillance. We investigated whether a liver-derived 186-gene signature previously associated with outcomes of patients with HCC is prognostic for patients newly diagnosed with cirrhosis but without HCC. Methods: We performed gene expression profile analysis of formalin-fixed needle biopsies from the livers of 216 patients with hepatitis C-related early-stage (Child-Pugh class A) cirrhosis who were prospectively followed for a median of 10 years at an Italian center. We evaluated whether the 186-gene signature was associated with death, progression of cirrhosis, and development of HCC. Results: Fifty-five (25%), 101 (47%), and 60 (28%) patients were classified as having poor-, intermediate-, and good-prognosis signatures, respectively. In multivariable Cox regression modeling, the poor-prognosis signature was significantly associated with death (P=.004), progression to advanced cirrhosis (P<.001), and development of HCC (P=.009). The 10-year rates of survival were 63%, 74%, and 85% and the annual incidences of HCC were 5.8%, 2.2%, and 1.5% for patients with poor-, intermediate-, and good-prognosis signatures, respectively. Conclusions: A 186-gene signature used to predict outcomes of patients with HCC is also associated with outcomes of patients with hepatitis C-related early-stage cirrhosis. This signature might be used to identify patients with cirrhosis in most need of surveillance and strategies to prevent their development of HCC. 216 liver biopsy specimens

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A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration.

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