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Cancer Res DOI:10.1158/0008-5472.CAN-09-1089

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

Publication TypeJournal Article
Year of Publication2009
AuthorsHoshida, Y, Nijman, SMB, Kobayashi, M, Chan, JA, Brunet, J-P, Chiang, DY, Villanueva, A, Newell, P, Ikeda, K, Hashimoto, M, Watanabe, G, Gabriel, S, Friedman, SL, Kumada, H, Llovet, JM, Golub, TR
JournalCancer Res
Date Published2009 Sep 15
Keywordsbeta Catenin, Carcinoma, Hepatocellular, Cell Line, Tumor, Cohort Studies, Gene Expression Profiling, Humans, Liver Neoplasms, Signal Transduction, Transforming Growth Factor beta, Wnt Proteins

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.


Alternate JournalCancer Res.
PubMed ID19723656
PubMed Central IDPMC3549578
Grant List5U54 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