Identification of Gene Signature as Diagnostic and Prognostic Blood Biomarker for Early Hepatocellular Carcinoma Using Integrated Cross-Species Transcriptomic and Network Analyses.

Olfat Al-Harazi,Ali Saeed Al Zahrani,Maha Al-Eid,Ibrahim H Kaya,Mohammed Al Sebayel,Lina Alfantoukh,Dilek Colak,Namik Kaya

doi:10.3389/fgene.2021.710049

Abstract

Background: Hepatocellular carcinoma (HCC) is considered the most common type of liver cancer and the fourth leading cause of cancer-related deaths in the world. Since the disease is usually diagnosed at advanced stages, it has poor prognosis. Therefore, reliable biomarkers are urgently needed for early diagnosis and prognostic assessment. Methods: We used genome-wide gene expression profiling datasets from human and rat early HCC (eHCC) samples to perform integrated genomic and network-based analyses, and discovered gene markers that are expressed in blood and conserved in both species. We then used independent gene expression profiling datasets for peripheral blood mononuclear cells (PBMCs) for eHCC patients and from The Cancer Genome Atlas (TCGA) database to estimate the diagnostic and prognostic performance of the identified gene signature. Furthermore, we performed functional enrichment, interaction networks and pathway analyses. Results: We identified 41 significant genes that are expressed in blood and conserved across species in eHCC. We used comprehensive clinical data from over 600 patients with HCC to verify the diagnostic and prognostic value of 41-gene-signature. We developed a prognostic model and a risk score using the 41-geneset that showed that a high prognostic index is linked to a worse disease outcome. Furthermore, our 41-gene signature predicted disease outcome independently of other clinical factors in multivariate regression analysis. Our data reveals a number of cancer-related pathways and hub genes, including EIF4E, H2AFX, CREB1, GSK3B, TGFBR1, and CCNA2, that may be essential for eHCC progression and confirm our gene signature’s ability to detect the disease in its early stages in patients’ biological fluids instead of invasive procedures and its prognostic potential. Conclusion: Our findings indicate that integrated cross-species genomic and network analysis may provide reliable markers that are associated with eHCC that may lead to better diagnosis, prognosis, and treatment options.

Highlights

Hepatocellular carcinoma (HCC) is a leading cause of cancerrelated deaths worldwide (Bray et al, 2018; Yang et al, 2019a; Villanueva, 2019)
We analyzed human HCC data, focusing only on patients with early HCC, from Chiang et al (Chiang et al, 2008) and Wurmbach et al (Wurmbach et al, 2007), that revealed 4,289 and 5,342 differentially expressed gene (DEG) that were significantly dysregulated in patients compared to normal controls
The Venn diagram approach indicated 2,796 DEGs were shared by both human datasets and 54 of which were conserved across both species (Figure 1)

Summary

Introduction

Hepatocellular carcinoma (HCC) is a leading cause of cancerrelated deaths worldwide (Bray et al, 2018; Yang et al, 2019a; Villanueva, 2019). The disease is mostly diagnosed at advanced stages, and has poor prognosis. HCC is usually diagnosed using serum alpha-fetoprotein (AFP) and ultrasound (Schütte et al, 2014; Tsuchiya et al, 2015) (Shi et al, 2014). There is a significant need to identify alternative or additional biomarkers that can be used in effectively diagnosing patients in an early tumor stage. Hepatocellular carcinoma (HCC) is considered the most common type of liver cancer and the fourth leading cause of cancer-related deaths in the world. Since the disease is usually diagnosed at advanced stages, it has poor prognosis. Reliable biomarkers are urgently needed for early diagnosis and prognostic assessment

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Conclusion