A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection

David Y. Zhang, Nicolas Goossens, Jinsheng Guo, Ming Chao Tsai, Hsin I. Chou, Civan Altunkaynak, Angelo Sangiovanni, Massimo Iavarone, Massomo Colombo, Masahiro Kobayashi, Hiromitsu Kumada, Augusto Villanueva, Josep M. Llovet, Yujin Hoshida, Scott L. Friedman

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Objective We used an informatics approach to identify and validate genes whose expression is unique to hepatic stellate cells and assessed the prognostic capability of their expression in cirrhosis. Design We defined a hepatic stellate cell gene signature by comparing stellate, immune and hepatic transcriptome profiles. We then created a prognostic index using a combination of hepatic stellate cell signature expression and clinical variables. This signature was derived in a retrospectiveprospective cohort of hepatitis C-related early-stage cirrhosis (prognostic index derivation set) and validated in an independent retrospective cohort of patients with postresection hepatocellular carcinoma (HCC). We then examined the association between hepatic stellate cell signature expression and decompensation, HCC development, progression of Child-Pugh class and survival. Results The 122-gene hepatic stellate cell signature consists of genes encoding extracellular matrix proteins and developmental factors and correlates with the extent of fibrosis in human, mouse and rat datasets. Importantly, association of clinical prognostic variables with overall survival was improved by adding the signature; we used these results to define a prognostic index in the derivation set. In the validation set, the same prognostic index was associated with overall survival. The prognostic index was associated with decompensation, HCC and progression of Child-Pugh class in the derivation set, and HCC recurrence in the validation set. Conclusions This work highlights the unique transcriptional niche of stellate cells, and identifies potential stellate cell targets for tracking, targeting and isolation. Hepatic stellate cell signature expression may identify patients with HCV cirrhosis or postresection HCC with poor prognosis.

Original languageEnglish (US)
Pages (from-to)1754-1764
Number of pages11
JournalGut
Volume65
Issue number10
DOIs
StatePublished - Oct 1 2016
Externally publishedYes

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Hepatic Stellate Cells
Hepatitis C
Transcriptome
Hepatocellular Carcinoma
Fibrosis
Survival
Cell Tracking
Genes
Informatics
Cell Separation
Extracellular Matrix Proteins
Child Development
Gene Expression
Recurrence
Liver

ASJC Scopus subject areas

  • Gastroenterology

Cite this

A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection. / Zhang, David Y.; Goossens, Nicolas; Guo, Jinsheng; Tsai, Ming Chao; Chou, Hsin I.; Altunkaynak, Civan; Sangiovanni, Angelo; Iavarone, Massimo; Colombo, Massomo; Kobayashi, Masahiro; Kumada, Hiromitsu; Villanueva, Augusto; Llovet, Josep M.; Hoshida, Yujin; Friedman, Scott L.

In: Gut, Vol. 65, No. 10, 01.10.2016, p. 1754-1764.

Research output: Contribution to journalArticle

Zhang, DY, Goossens, N, Guo, J, Tsai, MC, Chou, HI, Altunkaynak, C, Sangiovanni, A, Iavarone, M, Colombo, M, Kobayashi, M, Kumada, H, Villanueva, A, Llovet, JM, Hoshida, Y & Friedman, SL 2016, 'A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection', Gut, vol. 65, no. 10, pp. 1754-1764. https://doi.org/10.1136/gutjnl-2015-309655
Zhang, David Y. ; Goossens, Nicolas ; Guo, Jinsheng ; Tsai, Ming Chao ; Chou, Hsin I. ; Altunkaynak, Civan ; Sangiovanni, Angelo ; Iavarone, Massimo ; Colombo, Massomo ; Kobayashi, Masahiro ; Kumada, Hiromitsu ; Villanueva, Augusto ; Llovet, Josep M. ; Hoshida, Yujin ; Friedman, Scott L. / A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection. In: Gut. 2016 ; Vol. 65, No. 10. pp. 1754-1764.
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abstract = "Objective We used an informatics approach to identify and validate genes whose expression is unique to hepatic stellate cells and assessed the prognostic capability of their expression in cirrhosis. Design We defined a hepatic stellate cell gene signature by comparing stellate, immune and hepatic transcriptome profiles. We then created a prognostic index using a combination of hepatic stellate cell signature expression and clinical variables. This signature was derived in a retrospectiveprospective cohort of hepatitis C-related early-stage cirrhosis (prognostic index derivation set) and validated in an independent retrospective cohort of patients with postresection hepatocellular carcinoma (HCC). We then examined the association between hepatic stellate cell signature expression and decompensation, HCC development, progression of Child-Pugh class and survival. Results The 122-gene hepatic stellate cell signature consists of genes encoding extracellular matrix proteins and developmental factors and correlates with the extent of fibrosis in human, mouse and rat datasets. Importantly, association of clinical prognostic variables with overall survival was improved by adding the signature; we used these results to define a prognostic index in the derivation set. In the validation set, the same prognostic index was associated with overall survival. The prognostic index was associated with decompensation, HCC and progression of Child-Pugh class in the derivation set, and HCC recurrence in the validation set. Conclusions This work highlights the unique transcriptional niche of stellate cells, and identifies potential stellate cell targets for tracking, targeting and isolation. Hepatic stellate cell signature expression may identify patients with HCV cirrhosis or postresection HCC with poor prognosis.",
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T1 - A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection

AU - Zhang, David Y.

AU - Goossens, Nicolas

AU - Guo, Jinsheng

AU - Tsai, Ming Chao

AU - Chou, Hsin I.

AU - Altunkaynak, Civan

AU - Sangiovanni, Angelo

AU - Iavarone, Massimo

AU - Colombo, Massomo

AU - Kobayashi, Masahiro

AU - Kumada, Hiromitsu

AU - Villanueva, Augusto

AU - Llovet, Josep M.

AU - Hoshida, Yujin

AU - Friedman, Scott L.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Objective We used an informatics approach to identify and validate genes whose expression is unique to hepatic stellate cells and assessed the prognostic capability of their expression in cirrhosis. Design We defined a hepatic stellate cell gene signature by comparing stellate, immune and hepatic transcriptome profiles. We then created a prognostic index using a combination of hepatic stellate cell signature expression and clinical variables. This signature was derived in a retrospectiveprospective cohort of hepatitis C-related early-stage cirrhosis (prognostic index derivation set) and validated in an independent retrospective cohort of patients with postresection hepatocellular carcinoma (HCC). We then examined the association between hepatic stellate cell signature expression and decompensation, HCC development, progression of Child-Pugh class and survival. Results The 122-gene hepatic stellate cell signature consists of genes encoding extracellular matrix proteins and developmental factors and correlates with the extent of fibrosis in human, mouse and rat datasets. Importantly, association of clinical prognostic variables with overall survival was improved by adding the signature; we used these results to define a prognostic index in the derivation set. In the validation set, the same prognostic index was associated with overall survival. The prognostic index was associated with decompensation, HCC and progression of Child-Pugh class in the derivation set, and HCC recurrence in the validation set. Conclusions This work highlights the unique transcriptional niche of stellate cells, and identifies potential stellate cell targets for tracking, targeting and isolation. Hepatic stellate cell signature expression may identify patients with HCV cirrhosis or postresection HCC with poor prognosis.

AB - Objective We used an informatics approach to identify and validate genes whose expression is unique to hepatic stellate cells and assessed the prognostic capability of their expression in cirrhosis. Design We defined a hepatic stellate cell gene signature by comparing stellate, immune and hepatic transcriptome profiles. We then created a prognostic index using a combination of hepatic stellate cell signature expression and clinical variables. This signature was derived in a retrospectiveprospective cohort of hepatitis C-related early-stage cirrhosis (prognostic index derivation set) and validated in an independent retrospective cohort of patients with postresection hepatocellular carcinoma (HCC). We then examined the association between hepatic stellate cell signature expression and decompensation, HCC development, progression of Child-Pugh class and survival. Results The 122-gene hepatic stellate cell signature consists of genes encoding extracellular matrix proteins and developmental factors and correlates with the extent of fibrosis in human, mouse and rat datasets. Importantly, association of clinical prognostic variables with overall survival was improved by adding the signature; we used these results to define a prognostic index in the derivation set. In the validation set, the same prognostic index was associated with overall survival. The prognostic index was associated with decompensation, HCC and progression of Child-Pugh class in the derivation set, and HCC recurrence in the validation set. Conclusions This work highlights the unique transcriptional niche of stellate cells, and identifies potential stellate cell targets for tracking, targeting and isolation. Hepatic stellate cell signature expression may identify patients with HCV cirrhosis or postresection HCC with poor prognosis.

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