Identification of hedgehog signaling as a potential oncogenic driver in an aggressive subclass of human hepatocellular carcinoma: A reanalysis of the TCGA cohort

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Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous disease and the second most common cause of cancer-related death worldwide. Marked developments in genomic technologies helped scientists to understand the heterogeneity of HCC and identified multiple HCC-related molecular subclasses. An integrative analysis of genomic datasets including 196 patients from The Cancer Genome Atlas (TCGA) group has recently reported a new HCC subclass, which contains three subgroups (iCluster1, iCluster2, and iCluster3). However, the transcriptional molecular characteristics underlying the iClusters have not been thoroughly investigated. Herein, we identified a more aggressive subset of HCC patients in the iCluster1, and re-clustered the TCGA samples into novel HCC subclasses referred to as aggressive (Ag), moderate-aggressive (M-Ag), and less-aggressive (L-Ag) subclasses. The Ag subclass had a greater predictive power than the TCGA iCluster1, and a higher level of alpha fetoprotein, microscopic vascular invasion, immune infiltration, isocitrate dehydrogenase 1/2 mutation status, and a worse survival than M-Ag and L-Ag subclasses. Global transcriptomic analysis showed that activation of hedgehog signaling in the Ag subclass may play key roles in tumor development of aggressive HCC. GLI1, a key transcriptional regulator of hedgehog signaling upregulated in the Ag subclass, was correlated with poor prognosis of HCC, and may be a potential prognostic biomarker and therapeutic target for Ag subclass HCC patients.

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