Identification of special key genes for alcohol-related hepatocellular carcinoma through bioinformatic analysis

Abstract

BackgroundAlcohol-related hepatocellular carcinoma (HCC) was reported to be diagnosed at a later stage, but the mechanism was unknown. This study aimed to identify special key genes (SKGs) during alcohol-related HCC development and progression.MethodsThe mRNA data of 369 HCC patients and the clinical information were downloaded from the Cancer Genome Atlas project (TCGA). The 310 patients with certain HCC-related risk factors were included for analysis and divided into seven groups according to the risk factors. Survival analyses were applied for the HCC patients of different groups. The patients with hepatitis B virus or hepatitis C virus infection only were combined into the HCC-V group for further analysis. The differentially expressed genes (DEGs) between the HCCs with alcohol consumption only (HCC-A) and HCC-V tumors were identified through limma package in R with cutoff criteria│log2 fold change (logFC)|>1.0 and p < 0.05. The DEGs between eight alcohol-related HCCs and their paired normal livers of from the Gene Expression Omnibus (GEO) were identified through GEO2R (a built-in tool in GEO database) with cutoff criteria |logFC|> 2.0 and adj.p < 0.05. The intersection of the two sets of DEGs was considered SKGs which were then investigated for their specificity through comparisons between HCC-A and other four HCC groups. The SKGs were analyzed for their correlations with HCC-A stage and grade and their prognostic power for HCC-A patients. The expressional differences of the SKGs in the HCCs in whole were also investigated through Gene Expression Profiling Interactive Analysis (GEPIA). The SKGs in HCC were validated through Oncomine database analysis.ResultsPathological stage is an independent prognostic factor for HCC patients. HCC-A patients were diagnosed later than HCC patients with other risk factors. Ten SKGs were identified and nine of them were confirmed for their differences in paired samples of HCC-A patients. Three (SLC22A10, CD5L, and UROC1) and four (SLC22A10, UROC1, CSAG3, and CSMD1) confirmed genes were correlated with HCC-A stage and grade, respectively. SPP2 had a lower trend in HCC-A tumors and was negatively correlated with HCC-A stage and grade. The SKGs each was differentially expressed between HCC-A and at least one of other HCC groups. CD5L was identified to be favorable prognostic factor for overall survival while CSMD1 unfavorable prognostic factor for disease-free survival for HCC-A patients and HCC patients in whole. Through Oncomine database, the dysregulations of the SKGs in HCC and their clinical significance were confirmed.ConclusionThe poor prognosis of HCC-A patients might be due to their later diagnosis. The SKGs, especially the four stage-correlated genes (CD5L, SLC22A10, UROC1, and SPP2) might play important roles in HCC development, especially alcohol-related HCC development and progression. CD5L might be useful for overall survival and CSMD1 for disease-free survival predication in HCC, especially alcohol-related HCC.

Knowledge-based analyses reveal new candidate genes associated with risk of hepatitis B virus related hepatocellular carcinoma

“…UROC1 (p = 1.4E-3) encodes enzyme involved in histidine catabolism, metabolizing urocanic acid to formiminoglutamic acid. Zhang et al showed that UROC1 may play important roles in HCC development, especially alcohol-related HCC development and progression [52].…”

Peer Review #2 of "Whole genome sequencing analysis identifies recurrent structural alterations in esophageal squamous cell carcinoma (v0.1)"

“…Recurrent SVs in CSMD1, WWOX, ERC1, PDE4D and SHANK2 were also identified in five tumor samples. The CUB and Sushi multiple domains 1 (CSMD1) is a tumor suppressor gene reported to be associated with poor prognosis in many cancer types including breast cancer, gastric cancer, head and neck squamous cell carcinoma (HNSCC), and hepatocellular carcinoma (Deng et al, 2012) , (Zhang et al, 2019) , (Jung et al, 2018). Deletion of WWOX, a tumor suppressor gene, is frequent in esophageal adenocarcinoma (32%) and stomach adenocarcinoma (30.2%) and also observed in other human cancer types such as colon adenocarcinoma, bladder urothelial carcinoma and lung adenocarcinoma (Hussain et al, 2019).…”

<p>Genetic Biomarkers For Hepatocellular Carcinoma In The Era Of Precision Medicine</p>

“…It was reported that mutations in TRET promoter, CTNNB1, ARID1A are more common in alcohol-related HCC incidences 26. A recent study identified 5 up-regulated genes (CSMD1, MAGEA3, MAGEA6, CSAG1, and CSAG3) and 4 down-regulated genes (CD5L,UROC1, IGF2, and SLC22A10) that were associated with alcohol-related HCC 27…”