Inactivation of Hippo Pathway Is Significantly Associated with Poor Prognosis in Hepatocellular Carcinoma

Abstract

BIOLOGY OF HUMAN TUMORS| FEBRUARY 29 2016 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 Cha; In-Sun Chu; Randy L. Johnson; Yun-Yong Park; Ju-Seog Lee Crossmark: Check for Updates Author & Article Information Clin Cancer Res (2016) 22 (5): 1256–1264. https://doi.org/10.1158/1078-0432.CCR-15-1447 Article history Split-Screen Views Icon Views PDF Share Icon Share Tools Icon Tools Search Site Article Versions Icon Versions 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.