Metabolic Pathways Enhancement Confers Poor Prognosis in p53 Exon Mutant Hepatocellular Carcinoma

Abstract

RNA-Sequencing (RNA-Seq), the most commonly used sequencing application tool, is not only a method for measuring gene expression but also an excellent media to detect important structural variants such as single nucleotide variants (SNVs), insertion/deletion (Indels), or fusion transcripts. The Cancer Genome Atlas (TCGA) contains genomic data from a variety of cancer types and also provides the raw data generated by TCGA consortium. p53 is among the top 10 somatic mutations associated with hepatocellular carcinoma (HCC). The aim of the present study was to analyze concordant different gene profiles and the priori defined set of genes based on p53 mutation status in HCC using RNA-Seq data. In the study, expression profile of 11 799 genes on 42 paired tumor and adjacent normal tissues was collected, processed, and further stratified by the mutated versus normal p53 expression. Furthermore, we used a knowledge-based approach Gene Set Enrichment Analysis (GSEA) to compare between normal and p53 mutation gene expression profiles. The statistical significance (nominal P value) of the enrichment score (ES) genes was calculated. The ranked gene list that reflects differential expression between p53 wild-type and mutant genotypes was then mapped to metabolic process by KEGG, an encyclopedia of genes and genomes to assign functional meanings. These approaches enable us to identify pathways and potential target gene/pathways that are highly expressed in p53 mutated HCC. Our analysis revealed 2 genes, the hexokinase 2 ( HK2) and Enolase 1 ( ENO1), were conspicuous of red pixel in the heatmap. To further explore the role of these genes in HCC, the overall survival plots by Kaplan-Meier method were performed for HK2 and ENO1 that revealed high HK2 and ENO1 expression in patients with HCC have poor prognosis. These results suggested that these glycolysis genes are associated with mutated-p53 in HCC that may contribute to poor prognosis. In this proof-of-concept study, we proposed an approach for identifying novel potential therapeutic targets in human HCC with mutated p53. These approaches can take advantage of the massive next-generation sequencing (NGS) data generated worldwide and make more out of it by exploring new potential therapeutic targets.

Impact of TP53 Mutations in Hepatocellular Carcinoma on Carcinogenesis, Diagnosis, Prognosis and Treatment

“…By inhibiting TAp63, mutant p53 can initiate a proinvasive transcription program [117,118], which might be one explanation for the poor prognosis related to mutant p53 in HCC [13,15,16], a fact which makes evaluation of the TP53 mutation status an important prognostic marker [153]. In conjunction with the TP53 mutation status, the immunoprognostic model suggested by Long et al [156], has the potential to provide a sensitive framework for accurate risk stratification.…”

“…In conjunction with the TP53 mutation status, the immunoprognostic model suggested by Long et al [156], has the potential to provide a sensitive framework for accurate risk stratification. Moreover, Chen et al [13] identified two genes, HK2 and ENO1 which are differentially expressed between WT vs. mutant p53 and demonstrated that overexpression going together with mutant p53 is related to inferior prognosis. Since both genes are involved in glycolysis they may contribute to ongoing inflammatory processes and thereby possibly trigger cancerogenesis.…”

“…With respect to chromosome stability status, hepatic tumors can be assigned to either of two groups: Tumors with a tendency to chromosome instability are typically HBV positive and poorly differentiated and frequently associated with mutations of the tumor suppressor gene TP53 (MIM# 191170) [13][14][15][16], while tumors that exhibit stable chromosomes are usually non-HBV and well-differentiated and are frequently found to be related to activated ß-catenin [17].…”

“…Assessment of concordant different gene profiles in HCC based on the TP53 mutation status identified two genes involved in glycolysis, the hexokinase 2 (HK2) and enolase 1 (ENO1), which are significantly overexpressed in HCC with mutant p53 [13]. Kaplan-Meier plots on OS for HK2 and ENO1 revealed that high expression levels correlate with a poor outcome.…”

“…Kaplan-Meier plots on OS for HK2 and ENO1 revealed that high expression levels correlate with a poor outcome. Because HCC is associated with persistent inflammation, as more than 90% of cases arise in the context of hepatic injury and inflammation [154], and since p53 has the potential to modulate the inflammatory microenvironment, tumor microenvironment, and tumor suppression [155], the authors suggest that overexpression of these glycolysis genes together with mutant p53 may directly contribute to the poor prognosis [13].…”