Integrative Transcriptome Analysis Reveals Common Molecular Subclasses of Human Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, and prior attempts to develop genomics-based classification for HCC have yielded highly divergent results, indicating difficulty to identify unified molecular anatomy. We performed a meta-analysis of gene expression profiles in datasets from 8 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 3 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 TGF-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 of multiple datasets to define a robust molecular taxonomy of the disease.

Defeating EpCAM+ liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma

“…This is partly due to a lack of effective chemotherapeutic options for patients with advanced-stage disease [3]. Various molecular profiling approaches have been used to identify potential therapeutic targets which are specifically activated in HCC [4][5][6][7][8]. Some studies have indicated the importance of evaluating ''stemness'' in HCC; it reflects the malignant nature of the tumor and closely correlates with a poor prognosis after surgery [9][10][11][12].…”

Systemic therapy for advanced hepatocellular carcinoma: an update

“…The past decade has seen multiple negative trials, many of which have not been guided by our understanding of genetic pathways in HCC. Current efforts should be directed toward the development of biomarker-enriched clinical trials, as well as drugs that target key oncogenic pathways with a better understanding of the tumor biology and genetics (65)(66)(67).…”

Primary and Metastatic Tumours of the Liver: Expanding Scope of Morphological and Immunohistochemical Details in the Biopsy

“…The subtypes are distinguished by high proliferation and chromosomal instability; by activation of Wnt signalling pathway and by interferon signalling due to tumour-infiltrating cells [70][71][72][73][74][75][76][77].…”