Inactivation of hippo pathway is significantly associated with poor prognosis in hepatocellular carcinoma

Bo Hwa Sohn, Jae Jun Shim, Sang Bae Kim, Kyu Yun Jang, Soo Mi Kim, Ji Hoon Kim, Jun Eul Hwang, Hee Jin Jang, Hyun Sung Lee, Sang Cheol Kim, Woojin Jeong, Sung Soo Kim, Eun Sung Park, Jeonghoon Heo, Yoon Jun Kim, Dae Ghon Kim, Sun Hee Leem, Ahmed Kaseb, Manal M. Hassan, Minse ChaIn Sun Chu, Randy L. Johnson, Yun Yong Park, Ju Seog Lee

Research output: Contribution to journalArticle

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Abstract

Purpose: The Hippo pathway is a tumor suppressor in the liver. However, the clinical significance of Hippo pathway inactivation in HCC is not clearly defined. We analyzed genomic data from human and mouse tissues to determine clinical relevance of Hippo pathway inactivation in HCC. Experimental Design: We analyzed gene expression data from Mst1/2-/- and Sav1-/- mice and identified a 610-gene expression signature reflecting Hippo pathway inactivation in the liver [silence of Hippo (SOH) signature]. By integrating gene expression data from mouse models with those from human HCC tissues, we developed a prediction model that could identify HCC patients with an inactivated Hippo pathway and used it to test its significance in HCC patients, via univariate and multivariate Cox analyses. Results: HCC patients (National Cancer Institute cohort, n = 113) with the SOH signature had a significantly poorer prognosis than those without the SOH signature [P < 0.001 for overall survival (OS)]. The significant association of the signature with poor prognosis was further validated in the Korean (n = 100, P = 0.006 for OS) and Fudan University cohorts (n = 242, P = 0.001 for OS). On multivariate analysis, the signature was an independent predictor of recurrence-free survival (HR, 1.6; 95% confidence interval, 1.12-2.28: P = 0.008). We also demonstrated significant concordance between the SOH HCC subtype and the hepatic stem cell HCC subtype that had been identified in a previous study (P < 0.001). Conclusions: Inactivation of the Hippo pathway in HCC is significantly associated with poor prognosis. Clin Cancer Res; 22(5); 1256-64.

Original languageEnglish
Pages (from-to)1256-1264
Number of pages9
JournalClinical Cancer Research
Volume22
Issue number5
DOIs
Publication statusPublished - 2016 Mar 1

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Hepatocellular Carcinoma
Survival
Multivariate Analysis
Gene Expression
National Cancer Institute (U.S.)
Liver
Transcriptome
Hepatocytes
Neoplasms
Research Design
Stem Cells
Confidence Intervals
Recurrence

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Inactivation of hippo pathway is significantly associated with poor prognosis in hepatocellular carcinoma. / Sohn, Bo Hwa; Shim, Jae Jun; Kim, Sang Bae; Jang, Kyu Yun; Kim, Soo Mi; Kim, Ji Hoon; Hwang, Jun Eul; Jang, Hee Jin; Lee, Hyun Sung; Kim, Sang Cheol; Jeong, Woojin; Kim, Sung Soo; Park, Eun Sung; Heo, Jeonghoon; Kim, Yoon Jun; Kim, Dae Ghon; Leem, Sun Hee; Kaseb, Ahmed; Hassan, Manal M.; Cha, Minse; Chu, In Sun; Johnson, Randy L.; Park, Yun Yong; Lee, Ju Seog.

In: Clinical Cancer Research, Vol. 22, No. 5, 01.03.2016, p. 1256-1264.

Research output: Contribution to journalArticle

Sohn, BH, Shim, JJ, Kim, SB, Jang, KY, Kim, SM, Kim, JH, Hwang, JE, Jang, HJ, Lee, HS, Kim, SC, Jeong, W, Kim, SS, Park, ES, Heo, J, Kim, YJ, Kim, DG, Leem, SH, Kaseb, A, Hassan, MM, Cha, M, Chu, IS, Johnson, RL, Park, YY & Lee, JS 2016, 'Inactivation of hippo pathway is significantly associated with poor prognosis in hepatocellular carcinoma', Clinical Cancer Research, vol. 22, no. 5, pp. 1256-1264. https://doi.org/10.1158/1078-0432.CCR-15-1447
Sohn, Bo Hwa ; Shim, Jae Jun ; Kim, Sang Bae ; Jang, Kyu Yun ; Kim, Soo Mi ; Kim, Ji Hoon ; Hwang, Jun Eul ; Jang, Hee Jin ; Lee, Hyun Sung ; Kim, Sang Cheol ; Jeong, Woojin ; Kim, Sung Soo ; Park, Eun Sung ; Heo, Jeonghoon ; Kim, Yoon Jun ; Kim, Dae Ghon ; Leem, Sun Hee ; Kaseb, Ahmed ; Hassan, Manal M. ; Cha, Minse ; Chu, In Sun ; Johnson, Randy L. ; Park, Yun Yong ; Lee, Ju Seog. / Inactivation of hippo pathway is significantly associated with poor prognosis in hepatocellular carcinoma. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 5. pp. 1256-1264.
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abstract = "Purpose: The Hippo pathway is a tumor suppressor in the liver. However, the clinical significance of Hippo pathway inactivation in HCC is not clearly defined. We analyzed genomic data from human and mouse tissues to determine clinical relevance of Hippo pathway inactivation in HCC. Experimental Design: We analyzed gene expression data from Mst1/2-/- and Sav1-/- mice and identified a 610-gene expression signature reflecting Hippo pathway inactivation in the liver [silence of Hippo (SOH) signature]. By integrating gene expression data from mouse models with those from human HCC tissues, we developed a prediction model that could identify HCC patients with an inactivated Hippo pathway and used it to test its significance in HCC patients, via univariate and multivariate Cox analyses. Results: HCC patients (National Cancer Institute cohort, n = 113) with the SOH signature had a significantly poorer prognosis than those without the SOH signature [P < 0.001 for overall survival (OS)]. The significant association of the signature with poor prognosis was further validated in the Korean (n = 100, P = 0.006 for OS) and Fudan University cohorts (n = 242, P = 0.001 for OS). On multivariate analysis, the signature was an independent predictor of recurrence-free survival (HR, 1.6; 95{\%} confidence interval, 1.12-2.28: P = 0.008). We also demonstrated significant concordance between the SOH HCC subtype and the hepatic stem cell HCC subtype that had been identified in a previous study (P < 0.001). Conclusions: Inactivation of the Hippo pathway in HCC is significantly associated with poor prognosis. Clin Cancer Res; 22(5); 1256-64.",
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T1 - Inactivation of hippo pathway is significantly associated with poor prognosis in hepatocellular carcinoma

AU - Sohn, Bo Hwa

AU - Shim, Jae Jun

AU - Kim, Sang Bae

AU - Jang, Kyu Yun

AU - Kim, Soo Mi

AU - Kim, Ji Hoon

AU - Hwang, Jun Eul

AU - Jang, Hee Jin

AU - Lee, Hyun Sung

AU - Kim, Sang Cheol

AU - Jeong, Woojin

AU - Kim, Sung Soo

AU - Park, Eun Sung

AU - Heo, Jeonghoon

AU - Kim, Yoon Jun

AU - Kim, Dae Ghon

AU - Leem, Sun Hee

AU - Kaseb, Ahmed

AU - Hassan, Manal M.

AU - Cha, Minse

AU - Chu, In Sun

AU - Johnson, Randy L.

AU - Park, Yun Yong

AU - Lee, Ju Seog

PY - 2016/3/1

Y1 - 2016/3/1

N2 - Purpose: The Hippo pathway is a tumor suppressor in the liver. However, the clinical significance of Hippo pathway inactivation in HCC is not clearly defined. We analyzed genomic data from human and mouse tissues to determine clinical relevance of Hippo pathway inactivation in HCC. Experimental Design: We analyzed gene expression data from Mst1/2-/- and Sav1-/- mice and identified a 610-gene expression signature reflecting Hippo pathway inactivation in the liver [silence of Hippo (SOH) signature]. By integrating gene expression data from mouse models with those from human HCC tissues, we developed a prediction model that could identify HCC patients with an inactivated Hippo pathway and used it to test its significance in HCC patients, via univariate and multivariate Cox analyses. Results: HCC patients (National Cancer Institute cohort, n = 113) with the SOH signature had a significantly poorer prognosis than those without the SOH signature [P < 0.001 for overall survival (OS)]. The significant association of the signature with poor prognosis was further validated in the Korean (n = 100, P = 0.006 for OS) and Fudan University cohorts (n = 242, P = 0.001 for OS). On multivariate analysis, the signature was an independent predictor of recurrence-free survival (HR, 1.6; 95% confidence interval, 1.12-2.28: P = 0.008). We also demonstrated significant concordance between the SOH HCC subtype and the hepatic stem cell HCC subtype that had been identified in a previous study (P < 0.001). Conclusions: Inactivation of the Hippo pathway in HCC is significantly associated with poor prognosis. Clin Cancer Res; 22(5); 1256-64.

AB - Purpose: The Hippo pathway is a tumor suppressor in the liver. However, the clinical significance of Hippo pathway inactivation in HCC is not clearly defined. We analyzed genomic data from human and mouse tissues to determine clinical relevance of Hippo pathway inactivation in HCC. Experimental Design: We analyzed gene expression data from Mst1/2-/- and Sav1-/- mice and identified a 610-gene expression signature reflecting Hippo pathway inactivation in the liver [silence of Hippo (SOH) signature]. By integrating gene expression data from mouse models with those from human HCC tissues, we developed a prediction model that could identify HCC patients with an inactivated Hippo pathway and used it to test its significance in HCC patients, via univariate and multivariate Cox analyses. Results: HCC patients (National Cancer Institute cohort, n = 113) with the SOH signature had a significantly poorer prognosis than those without the SOH signature [P < 0.001 for overall survival (OS)]. The significant association of the signature with poor prognosis was further validated in the Korean (n = 100, P = 0.006 for OS) and Fudan University cohorts (n = 242, P = 0.001 for OS). On multivariate analysis, the signature was an independent predictor of recurrence-free survival (HR, 1.6; 95% confidence interval, 1.12-2.28: P = 0.008). We also demonstrated significant concordance between the SOH HCC subtype and the hepatic stem cell HCC subtype that had been identified in a previous study (P < 0.001). Conclusions: Inactivation of the Hippo pathway in HCC is significantly associated with poor prognosis. Clin Cancer Res; 22(5); 1256-64.

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