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Liver sinusoidal scores: a new tool for the diagnosis and prognosis of chronic liver disease

ABSTRACT: Background and Aims: Sinusoidal cells drive the progression of chronic liver disease (CLD). Therefore, novel biomarkers for CLD should reflect the state of sinusoidal cells. However, the liver is mainly constituted from hepatocytes (80-90% of cells), while sinusoidal cells only represent the 10% of the cellular populations. Therefore, determination of biomarkers from plasma or bulk transcriptomics underrepresents smaller sinusoidal cell subpopulations, such as liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), and macrophages (MPs). On the other hand, recent studies performing single-cell sequencing allow for finer phenotype determination, but these analyses are too expensive for routine implementation in patient care. The aim of this study is to propose biologically-relevant markers of liver sinusoidal phenotype for the diagnosis and prognosis of CLDs. Methods: We estimated the relevant sinusoidal cell subpopulations in an internal cohort of 11 controls and 12 cirrhotic livers by gene deconvolution. Then, we reanalyzed published single-cell sequencing data in order to find a gene signature specific to these subpopulations. We combined the expression of these sinusoidal genes into 3 sinusoidal scores (endothelial, mesenchymal and macrophage) correlating with patient phenotypes. The ability of these scores to classify patients and predict fibrosis progression, regression and clinical decompensation was assessed in an internal cohort of 113 patients and further validated in 3 external cohorts for a total of 1008 patients with F3-F4 CLD (Simtuzumab, ATLAS & STELLAR trials). Results: We obtained a sinusoidal gene signature which was more specific for than traditional markers of LSEC capillarization, HSC activation and macrophage polarization. The three sinusoidal scores generated with these gene signatures were significantly higher in those patients with worse clinical parameters in our internal cohort and in the external validation cohort. The sinusoidal scores at baseline were significantly higher in patients that progressed from F3 to F4 fibrosis stage after 96 weeks of follow-up compared to those that stayed at F3. Similarly, the baseline sinusoidal scores were significantly lower in those patients that regressed from F4 to F3 compared to those that stayed at F4. Finally, the scores were able to predict decompensation in the following 96 weeks of follow-up (AUROC = 0.98) in the validation cohort and correlated with conventional parameters for evaluation of clinical decompensation (HVPG, Child-Pugh and MELD). Conclusions: This sinusoidal gene panel could aid in the diagnosis and prognosis of patients with CLD and predict future complications of cirrhosis. This technique can be easily assessed by RT-PCR and could be a useful tool for clinical decision making in the future, possibly aiding in assessment of drug response or in choosing the most relevant cell target for therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280687 | GEO | 2026/04/15

REPOSITORIES: GEO

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Project description:OBJECTIVE: 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. DESIGN: 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/mm3), 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). RESULTS: 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). CONCLUSIONS: 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. 145 liver tissue needle biopsy specimens from U.S. HCV cirrhosis cohort patients with histologically proven cirrhosis lacking evidence and a history of hepatic decompensation or HCC.

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Project description:For developing a accurate prognostic signature for “pan-driver-gene-negative” LUAD, we employed whole genome microarray expression profiling as a discovery platform to identify candidate genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis based on whole-genome microarrays indicated that the Wnt/β-catenin pathway was activated in “pan-driver-gene-negative” LUAD. Furthermore, the Wnt/β-catenin-pathway-based gene expression profiles revealed 39 transcripts differentially expressed by diagnostic status, with 30 genes being upregulated and 9 downregulated. Finally, a Wnt/β-catenin-pathway-based signature (CSDW) comprising 4 genes (β-catenin, Wnt2b, DVL3 and SOX9) was developed to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter overall survival (hazard ratio [HR] 10·42, 6·46–16·79; p<0·001) than patients with low-risk scores. The CSDW performance was further validated in an internal cohort and two external cohorts. The protein expression levels of several hub genes, including β-catenin, SOX9, DVL3 and Wnt2b, were strongly correlated with lymphatic metastasis and distant organ metastasis. Furthermore, a nomogram comprising CSDW and other variables was generated to predict progression-free survival and overall survival in the training cohort and performed well in the three independent validation cohorts (C-index: 0·725, 0·697 and 0·693, respectively). For developing a accurate prognostic signature for “pan-driver-gene-negative” LUAD, we employed whole genome microarray expression profiling as a discovery platform to identify candidate genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis based on whole-genome microarrays indicated that the Wnt/β-catenin pathway was activated in “pan-driver-gene-negative” LUAD. Furthermore, the Wnt/β-catenin-pathway-based gene expression profiles revealed 39 transcripts differentially expressed by diagnostic status, with 30 genes being upregulated and 9 downregulated. Finally, a Wnt/β-catenin-pathway-based signature (CSDW) comprising 4 genes (β-catenin, Wnt2b, DVL3 and SOX9) was developed to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter overall survival (hazard ratio [HR] 10·42, 6·46–16·79; p<0·001) than patients with low-risk scores. The CSDW performance was further validated in an internal cohort and two external cohorts. The protein expression levels of several hub genes, including β-catenin, SOX9, DVL3 and Wnt2b, were strongly correlated with lymphatic metastasis and distant organ metastasis. Furthermore, a nomogram comprising CSDW and other variables was generated to predict progression-free survival and overall survival in the training cohort and performed well in the three independent validation cohorts (C-index: 0·725, 0·697 and 0·693, respectively).

Project description:OBJECTIVE: 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. DESIGN: 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/mm3), 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). RESULTS: 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). CONCLUSIONS: 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. Paired core needle liver biopsy specimens obtained with time interval ranging from 1 month to 7.5 years from three individuals, and liver tissues from right and left lobes of explanted liver with chronic HCV infection from one individual.

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Liver sinusoidal scores: a new tool for the diagnosis and prognosis of chronic liver disease

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