A Minimal Subset of Seven Genes Associated with Tumor Hepatocyte Differentiation Predicts a Poor Prognosis in Human Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a deadly cancer worldwide as a result of a frequent late diagnosis which limits the therapeutic options. Tumor progression in HCC is closely correlated with the dedifferentiation of hepatocytes, the main parenchymal cells in the liver. Here, we hypothesized that the expression level of genes reflecting the differentiation status of tumor hepatocytes could be clinically relevant in defining subsets of patients with different clinical outcomes. To test this hypothesis, an integrative transcriptomics approach was used to stratify a cohort of 139 HCC patients based on a gene expression signature established in vitro in the HepaRG cell line using well-controlled culture conditions recapitulating tumor hepatocyte differentiation. The HepaRG model was first validated by identifying a robust gene expression signature associated with hepatocyte differentiation and liver metabolism. In addition, the signature was able to distinguish specific developmental stages in mice. More importantly, the signature identified a subset of human HCC associated with a poor prognosis and cancer stem cell features. By using an independent HCC dataset (TCGA consortium), a minimal subset of seven differentiation-related genes was shown to predict a reduced overall survival, not only in patients with HCC but also in other types of cancers (e.g., kidney, pancreas, skin). In conclusion, the study identified a minimal subset of seven genes reflecting the differentiation status of tumor hepatocytes and clinically relevant for predicting the prognosis of HCC patients.

Transcriptomic evidence for tumor‐specific beneficial or adverse effects of TGFβ pathway inhibition on the prognosis of patients with liver cancer

“…Unsupervised GSEA was done with the whole C2 collection of curated gene sets from the molecular signatures database (MSigDB). Integration of transcriptomic data was conducted using publicly available HCC datasets ( GSE1898 , GSE4024 , and GSE14520 ), as previously described [ 15 , 16 , 19 ]. In total, two independent cohorts of HCC were analyzed.…”

The Molecular Mechanisms Underlying Onset and Progression of Liver Cancers

“…Apart from alternative splicing, several papers also shed light on different gene expression signatures derived from liver cancer cells. On this point, Desoteux and colleagues identify genes differently expressed according to the differentiation status of tumor hepatocytes, including a minimal subset of seven genes predicting a poor prognosis in patients with HCC [5]. O'Brien and colleagues investigate the importance of estrogen receptor 1 (Esr1) in the development of HCC in female mice [6].…”