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

Lindsay Y. King, Claudia Canasto-Chibuque, Kara B. Johnson, Shun Yip, Xintong Chen, Kensuke Kojima, Manjeet Deshmukh, Anu Venkatesh, Poh Seng Tan, Xiaochen Sun, Augusto Villanueva, Angelo Sangiovanni, Venugopalan Nair, Milind Mahajan, Masahiro Kobayashi, Hiromitsu Kumada, Massimo Iavarone, Massimo Colombo, Maria Isabel Fiel, Scott L. FriedmanJosep M. Llovet, Raymond T. Chung, Yujin Hoshida

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1296-1302
Number of pages7
JournalGut
Volume64
Issue number8
DOIs
StatePublished - Aug 1 2015
Externally publishedYes

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Hepatitis C
Fibrosis
Liver
Platelet Count
Bilirubin
Genes
Disease Progression
Hepatocellular Carcinoma
Clinical Trials
Genome

ASJC Scopus subject areas

  • Gastroenterology

Cite this

A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration. / King, Lindsay Y.; Canasto-Chibuque, Claudia; Johnson, Kara B.; Yip, Shun; Chen, Xintong; Kojima, Kensuke; Deshmukh, Manjeet; Venkatesh, Anu; Tan, Poh Seng; Sun, Xiaochen; Villanueva, Augusto; Sangiovanni, Angelo; Nair, Venugopalan; Mahajan, Milind; Kobayashi, Masahiro; Kumada, Hiromitsu; Iavarone, Massimo; Colombo, Massimo; Fiel, Maria Isabel; Friedman, Scott L.; Llovet, Josep M.; Chung, Raymond T.; Hoshida, Yujin.

In: Gut, Vol. 64, No. 8, 01.08.2015, p. 1296-1302.

Research output: Contribution to journalArticle

King, LY, Canasto-Chibuque, C, Johnson, KB, Yip, S, Chen, X, Kojima, K, Deshmukh, M, Venkatesh, A, Tan, PS, Sun, X, Villanueva, A, Sangiovanni, A, Nair, V, Mahajan, M, Kobayashi, M, Kumada, H, Iavarone, M, Colombo, M, Fiel, MI, Friedman, SL, Llovet, JM, Chung, RT & Hoshida, Y 2015, 'A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration', Gut, vol. 64, no. 8, pp. 1296-1302. https://doi.org/10.1136/gutjnl-2014-307862
King, Lindsay Y. ; Canasto-Chibuque, Claudia ; Johnson, Kara B. ; Yip, Shun ; Chen, Xintong ; Kojima, Kensuke ; Deshmukh, Manjeet ; Venkatesh, Anu ; Tan, Poh Seng ; Sun, Xiaochen ; Villanueva, Augusto ; Sangiovanni, Angelo ; Nair, Venugopalan ; Mahajan, Milind ; Kobayashi, Masahiro ; Kumada, Hiromitsu ; Iavarone, Massimo ; Colombo, Massimo ; Fiel, Maria Isabel ; Friedman, Scott L. ; Llovet, Josep M. ; Chung, Raymond T. ; Hoshida, Yujin. / A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration. In: Gut. 2015 ; Vol. 64, No. 8. pp. 1296-1302.
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abstract = "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.",
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T1 - A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration

AU - King, Lindsay Y.

AU - Canasto-Chibuque, Claudia

AU - Johnson, Kara B.

AU - Yip, Shun

AU - Chen, Xintong

AU - Kojima, Kensuke

AU - Deshmukh, Manjeet

AU - Venkatesh, Anu

AU - Tan, Poh Seng

AU - Sun, Xiaochen

AU - Villanueva, Augusto

AU - Sangiovanni, Angelo

AU - Nair, Venugopalan

AU - Mahajan, Milind

AU - Kobayashi, Masahiro

AU - Kumada, Hiromitsu

AU - Iavarone, Massimo

AU - Colombo, Massimo

AU - Fiel, Maria Isabel

AU - Friedman, Scott L.

AU - Llovet, Josep M.

AU - Chung, Raymond T.

AU - Hoshida, Yujin

PY - 2015/8/1

Y1 - 2015/8/1

N2 - 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.

AB - 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.

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