Integrative Transcriptome Analysis Reveals Common Molecular Subclasses of Human Hepatocellular Carcinoma

TLDR

Hepatocellular carcinoma is highly heterogeneous, and prior genomic classification attempts have produced divergent results, underscoring the challenge of defining a unified molecular anatomy. The study aimed to validate a real‑world classification system by profiling 118 formalin‑fixed, paraffin‑embedded HCC samples. Researchers performed a meta‑analysis of gene‑expression data from eight independent cohorts and 118 FFPE samples, encompassing 603 patients with hepatitis B or C from Western and Eastern regions. They identified three robust subclasses (S1, S2, S3) linked to clinical features; S1 showed WNT pathway activation driven by TGF‑β, S2 exhibited proliferation with MYC/AKT activation, and S3 reflected hepatocyte differentiation, establishing the first consensus gene‑expression–based taxonomy for HCC.

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.