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A Novel Scoring System for Gastric Cancer Risk Assessment Based on the Expression of Three CLIP4 DNA Methylation-Associated Genes

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A Novel Scoring System for Gastric Cancer Risk Assessment Based on the Expression of Three CLIP4 DNA Methylation-Associated Genes INTERNATIONAL JOURNAL OF ONCOLOGY 53: 633-643, 2018 A novel scoring system for gastric cancer risk assessment based on the expression of three CLIP4 DNA methylation-associated genes CHENGGONG HU, YONGFANG ZHOU, CHANG LIU and YAN KANG Department of Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China Received January 19, 2018; Accepted April 26, 2018 DOI: 10.3892/ijo.2018.4433 Abstract. Gastric cancer (GC) is the fifth most common cancer CLIP4 DNA methylation, and three prognostic signature genes, and the third leading cause of cancer-associated mortality claudin-11 (CLDN11), apolipoprotein D (APOD), and chordin worldwide. In the current study, comprehensive bioinformatic like 1 (CHRDL1), were used to establish a risk assessment analyses were performed to develop a novel scoring system system. The prognostic scoring system exhibited efficiency in for GC risk assessment based on CAP-Gly domain containing classifying patients with different prognoses, where the low- linker protein family member 4 (CLIP4) DNA methylation risk groups had significantly longer overall survival times than status. Two GC datasets with methylation sequencing informa- those in the high-risk groups. CLDN11, APOD and CHRDL1 tion and mRNA expression profiling were downloaded from exhibited reduced expression in the hypermethylation and low- the The Cancer Genome Atlas and Gene Expression Omnibus risk groups compare with the hypomethylation and high-risk databases. Differentially expressed genes (DEGs) between groups, respectively. Multivariate Cox analysis indicated that the CLIP4 hypermethylation and CLIP4 hypomethylation risk value could be used as an independent prognostic factor. groups were screened using the limma package in R 3.3.1, In functional analysis, six functional gene ontology terms and and survival analysis of these DEGs was performed using the five GSEA pathways were associated with CLDN11, APOD survival package. A risk scoring system was established via and CHRDL1. The results established the credibility of the regression factor-weighted gene expression based on linear scoring system in this study. Additionally, these three genes, combination to screen the most important genes associated which were significantly associated with CLIP4 DNA meth- with CLIP4 methylation and prognosis. Genes associated with ylation and GC risk assessment, were identified as potential high/low-risk value were selected using the limma package. prognostic biomarkers. Functional enrichment analysis of the top 500 DEGs that positively and negatively associated with risk values was Introduction performed using DAVID 6.8 online and the gene set enrich- ment analysis (GSEA) software. In total, 35 genes were Gastric cancer (GC) is the fifth most common cancer in both identified to be that significantly associated with prognosis and sexes and the third most common cause of cancer-associated mortality worldwide (1). Due to the advances in diagnostic and therapeutic approaches, long-term survival for patients with early stage of GC has improved; however, the outlook for Correspondence to: Dr Yan Kang, Department of Critical Care individuals with advanced GC is still disappointing because Medicine, West China Hospital of Sichuan University, 37 Guo Xue of poor prognosis and limited treatment options (2,3). Poor Xiang, Chengdu, Sichuan 610041, P.R. China prognosis is frequently explained by the lack of early diag- E-mail: [email protected] nostic biomarkers and effective therapeutic treatments (3). As the prognosis of GC is closely associated with the stage of Abbreviations: GC, gastric cancer; DEGs, differentially expressed the disease at diagnosis, novel diagnostic modalities for early genes; CLIP4, CAP-Gly domain containing linker protein family stages and novel therapeutics are urgently required (4). Several member 4; TCGA, The Cancer Genome Atlas; EGFR, epidermal growth diagnostic biomarkers, such as aberrantly methylated DNA, factor receptor; GEO, Gene Expression Omnibus; GO, gene ontology; have aided the diagnoses and disease monitoring efforts in GSEA, gene set enrichment analysis; BH, Benjamini-Hochberg; OS, GC. overall survival; KM, Kaplan-Meier; CLDN11, claudin-11, APOD, Changes in DNA methylation have crucial roles during the apolipoprotein D; CHRDL1, chordin-like 1; BMP, bone morphogenetic protein; BMPR, bone morphogenetic protein receptor early stages of GC; therefore, aberrant DNA methylation is highlighted as the main change differentiating GC subtypes Key words: gastric cancer, CAP-Gly domain containing linker from the very first stage (2,5,6). Over 550 studies have demon- protein family member 4 DNA methylation, gene expression, scoring strated that aberrant epigenetic changes of >100 genes have system, functional enrichment analysis crucial roles during the early stages of GC (7,8). For example, a recent report associated promoter methylation of CAP-Gly domain containing linker protein family member 4 (CLIP4) with the increase in severity of gastritis with no metaplasia to 634 HU et al: A novel scoring system for GC risk assessment gastritis with metaplasia and GC, which may be a potentially Table I. Information of samples in training and validation useful molecular tool for GC risk stratification in endoscopic datasets. biopsies (9). CLIP4, also known as UBASH3A or TULA, is a member of GSE30601 and the T-cell ubiquitin ligand family. These proteins can suppress TCGA GSE15460 T-cell signaling, facilitate growth factor withdrawal-induced Parameter (n=393) (n=157) apoptosis in T-cells and promote the accumulation of various activated target receptors, such as T-cell receptors and Age (mean ± SD) 65.761±10.706 63.242±12.607 epidermal growth factor receptors (EGFRs), which can induce Sex (male/female) 258/135 100/57 cell invasiveness and metastasis (10-12). Additionally, CLIP4 Stage (I/II/III/IV) 52/125/173/32 23/25/59/20 is involved in regulating the expression of several tumor-asso- Overall survival 438.88±384.35 699.88±728.17 ciated genes, such as spleen associated tyrosine kinase, a (mean ± SD) member of the protein tyrosine kinase family associated with Radiotherapy (yes/no) 77/366 cell motility and increased cell migration (13-15), and Cbl Chemotherapy (yes/no) 183/260 proto-oncogene, which downregulates EGFR and activates Targeted molecular therapy 190/253 the epithelial-mesenchymal transition-associated EGFR (yes/no) signaling pathway (10,16). CLIP4 expression is also suggested to stimulate tumor metastasis in certain tumor types (17). TCGA, The Cancer Genome Atlas; SD, standard deviation. Considering the involvement of CLIP4 in tumor metastasis and the association between its promoter methylation and GC, it is worth exploring the CLIP4 DNA methylation-associated genes that may facilitate further understanding of the func- methylation sequencing information (GSE30601; Illumina tion of CLIP4 in the pathogenesis of GC and provide potential HumanMethylation27 BeadChip; ncbi.nlm.nih.gov/geo/query/ diagnostic biomarkers for clinical treatment. acc.cgi?acc=GSE30601) and mRNA expression profiling data In the present study, large quantities of methylation (GSE15460; Affymetrix GeneChip Human Genome U133 sequencing information and the mRNA expression profiling Plus 2.0; ;ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE15460), data from GC samples published in The Cancer Genome was downloaded from the GEO database (18). The 157 GC Atlas (TCGA) database were used to screen out the signifi- patients consisted of 100 males and 57 females with cant differentially expressed genes (DEGs) associated with 63.242±12.607 years (mean ± SD). There were 23 stage I, 25 CLIP4 DNA methylation. A prognostic scoring system was stage II, 59 stage III and 20 stage IV cases, and the remaining established based on the screened genes and simultane- stages were unavailable. The average survival time for 81 ously validated by the datasets from the independent Gene patients was 699.88±728.17 days (mean ± SD). Information on Expression Omnibus (GEO) database. The reliability of the the samples in the validation dataset is summarized in Table I. prognostic scoring system was further validated by correla- tion analysis between clinical characteristics and prognosis. Selection of candidate expression factors. Samples were Functional enrichment analysis of DEGs related to prognosis divided into CLIP4 hypermethylation and CLIP4 hypomethyl- was performed using gene ontology (GO) and gene set enrich- ation groups according to the median CLIP4 methylated value ment analysis (GSEA). of 0.326. The gene expression differences between the two groups were compared using the limma package in the R soft- Materials and methods ware 3.3.1 (19), and genes with |log fold change (FC)| >1 and Benjamini-Hochberg (BH)-adjusted P<0.01 were considered to Samples and datasets. Information of the samples in the be significant DEGs. Subsequently, survival analysis associated training dataset. The training dataset, containing 393 GC with these DEGs was performed by Kaplan-Meier analysis and samples with both methylation sequencing information univariate Cox regression analysis using the ‘survidiff’ func- (Illumina Human Methylation 450 platform) and mRNA tion in the survival package of R 3.3.1 (20,21) and P<0.05 was expression profiling data (Illumina platform), was downloaded set as the significance threshold. As mortality of patients with from the TCGA database (https://portal.gdc.cancer.gov/) an overall survival (OS) of <30 days may due to other factors, on
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