Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma.

Cancer Res
Authors
Keywords
Abstract

Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, and prior attempts to develop genomic-based classification for HCC have yielded highly divergent results, indicating difficulty in identifying unified molecular anatomy. We performed a meta-analysis of gene expression profiles in data sets from eight independent patient cohorts across the world. In addition, aiming to establish the real world applicability of a classification system, we profiled 118 formalin-fixed, paraffin-embedded tissues from an additional patient cohort. A total of 603 patients were analyzed, representing the major etiologies of HCC (hepatitis B and C) collected from Western and Eastern countries. We observed three robust HCC subclasses (termed S1, S2, and S3), each correlated with clinical parameters such as tumor size, extent of cellular differentiation, and serum alpha-fetoprotein levels. An analysis of the components of the signatures indicated that S1 reflected aberrant activation of the WNT signaling pathway, S2 was characterized by proliferation as well as MYC and AKT activation, and S3 was associated with hepatocyte differentiation. Functional studies indicated that the WNT pathway activation signature characteristic of S1 tumors was not simply the result of beta-catenin mutation but rather was the result of transforming growth factor-beta activation, thus representing a new mechanism of WNT pathway activation in HCC. These experiments establish the first consensus classification framework for HCC based on gene expression profiles and highlight the power of integrating multiple data sets to define a robust molecular taxonomy of the disease.

Year of Publication
2009
Journal
Cancer Res
Volume
69
Issue
18
Pages
7385-92
Date Published
2009 Sep 15
ISSN
1538-7445
URL
DOI
10.1158/0008-5472.CAN-09-1089
PubMed ID
19723656
PubMed Central ID
PMC3549578
Links
Grant list
5U54 CA112962-03 / CA / NCI NIH HHS / United States
R01 DK076986 / DK / NIDDK NIH HHS / United States
Howard Hughes Medical Institute / United States
1R01DK076986 / DK / NIDDK NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States