A novel risk score model for stomach adenocarcinoma based on the expression levels of 10 genes
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- Published online on: December 9, 2019 https://doi.org/10.3892/ol.2019.11190
- Pages: 1351-1367
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Copyright: © Guan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Gastric cancer (GC) is currently the fifth most common type of cancer and the third leading cause of cancer-associated mortality worldwide among both sexes (1,2). Stomach adenocarcinoma (STAD) accounts for 95% of malignant GC cases (3). The incidence of GC increased annually in young Hispanic and US populations (20–49 years) between 2,000 and 2014 (4,5). Patients with advanced GC exhibit poor prognosis, which is frequently explained by a lack of early diagnostic biomarkers and effective treatment (6). As the prognosis of GC is associated with the stage of the disease at diagnosis, novel effective diagnostic tools for early stages of GC are urgently required (7).
The phenotypic alterations and the molecular mechanisms underlying GC have been increasingly elucidated, and the majority of researchers believe that GC is a multifactorial disease, the development of which involves various risk factors, such as Helicobacter pylori infection, smoking habits and dietary factors (8–10). With the advances in molecular biology and genetic detection techniques, the aberrant expression of certain genes, including miR-125b, −199a and −100 has been demonstrated to be significantly associated with the pathogenesis and prognosis of GC (11). However, the aberrant expression of a limited number of genes cannot accurately reflect the pathogenesis and prognosis of GC. Therefore, it may be clinically useful to develop statistical models for disease risk prediction and tools for subsequent risk assessment (12,13).
Risk assessment tools are considered to be able to help estimate the probability that a person with a specific set of risk factors will develop a disease of interest (13). These risk assessment tools can facilitate the identification of high-risk populations in relation to a disease and are useful in the subsequent clinical decision-making process for healthcare providers and patients (12). Risk assessment tools have been used to predict the outcome of a number of diseases, such as thromboembolism, Lynch syndrome and certain types of cancer, including GC (12,14–20). This indicates the potential to establish a risk assessment tool using valuable prognostic factors with predictive capacity. Wang et al (20) developed a 53-gene signature for predicting prognosis of patients with GC. Although the prognostic scoring system has been demonstrated to successfully predict patient overall survival, the detection of expression of these 53 genes in one patient at a time is a complicated task in the clinical setting. Therefore, further efforts to establish a prognostic prediction model with fewer genes are still warranted.
The present study aimed to use large amounts of mRNA expression profiling data from STAD samples to screen significantly differentially expressed genes (DEGs) and establish a risk score (RS) model based on the screened genes. The RS model was simultaneously validated by means of an independent dataset from another database and via a correlation analysis between clinical characteristics and prognosis. This RS model might provide a new tool for predicting the prognosis of patients with STAD.
Materials and methods
Analysis workflow
The steps of the workflow were as follows: i) High-throughput RNA sequencing (RNA-seq) expression profiles and clinical data from patients with STAD were downloaded from The Cancer Gene Atlas (TCGA) database (https://portal.gdc.cancer.gov) and to be used as a training dataset; ii) the samples in the training set were subdivided into tumor and control samples according to the clinical data and were subjected to screening to identify DEGs; iii) prognostic DEGs were identified in the training set by univariate Cox regression analysis; iv) the prognostic DEGs selected in the previous step were screened using the least absolute shrinkage and selection operator (LASSO) regularization regression algorithm (21), and the resulting genes were used to develop the RS model. The model validation and effectiveness evaluation were performed on an independent dataset retrieved from the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo); v) screening and stratified analysis of clinical factors were performed to identify independent prognostic risk factors; vi) screening of mRNA-seq data for DEGs and Gene Set Enrichment Analysis (GSEA) were performed in groups with different estimated prognosis. The overall analysis process is presented in Fig. 1.
Data
On April 8, 2018, the training dataset, comprising 348 samples with RNA-seq expression profile data and corresponding clinical information, was downloaded from TCGA. The 348 samples comprised 37 control samples and 311 STAD samples with survival times >6 months. The validation dataset GSE62254 (22), comprising 300 samples with RNA-seq expression profile data and the corresponding clinical information, was retrieved from the National Center for Biotechnology Information GEO database [platform GPL570 (HG-U133_Plus_2), Affymetrix Human Genome U133 Plus 2.0 Array]. The clinical information from the training and validation datasets is presented in Table I.
Screening of RNA-seq data for mRNAs with significant differential expression between groups with different prognosis
The edgeR package, version 3.20.9, of the R 3.4.0 language (http://bioconductor.org/packages/release/bioc/html/edgeR.html) (23) was used with the training dataset to identify significant differences in mRNA expression between the 311 STAD samples and 37 control samples. There were two thresholds selected: False discovery rate <0.05 and |log2(fold-change)| >0.5. According to the significant differences in mRNA expression between the training set samples, two-way hierarchical clustering analysis of the mRNA expression values was performed using pheatmap version 1.0.8 in R 3.4.0 (https://cran.r-project.org/web/packages/pheatmap/index.html) (24) according to a centered Pearson correlation algorithm (25).
Identification of prognosis-associated mRNAs and clinical factors
Cox regression analysis was performed on the 311 STAD tumor samples in the training dataset using survival package version 2.41.3 in R 3.4.0 (https://cran.r-project.org/web/packages/survival/index.html) (26,27) to screen the mRNAs and clinical factors for those significantly associated with overall survival time. The screening threshold was log-rank test P<0.05.
Establishment and evaluation of the risk assessment tool (RS model)
Selection of an optimal mRNA combination
Based on the identified prognosis-associated mRNAs, the optimal mRNA combination was identified by the LASSO regularization regression algorithm (21) in the penalized package, version 0.9.50 in R 3.4.0 (https://cran.r-project.org/web/packages/penalized/index.html) (28). Optimized parameter l in the screening model was determined through cyclic execution of 1,000 repetitions of cross-validation likelihood (CVL) algorithm (29).
Determination of the mRNA expression level cutoff
For each mRNA included in the optimal mRNA combination, the expression level cutoff value was determined using the X-Tile Software (https://medicine.yale.edu/lab/rimm/research/software.aspx) (30). Monte-Carlo P<0.05 was used as the threshold to determine the cut-off value. The status of each sample was determined according to the cut-off value of each mRNA; when the mRNA expression level in the sample was higher compared with the cut-off value, the status of this sample was defined as 1; otherwise, the status of this sample was defined as 0. Subsequently, a sample RS model was constructed using a linear combination of mRNA expression levels weighted by a regression coefficient (β) (obtained using the Cox regression model); thus, a prognostic index of each sample (i.e., RS) was calculated as follows: RS = Σ [β (mRNAn) × status (mRNAn)]. The RS of each sample in the training set was calculated, and the training samples were divided into prognostic high- (samples with an RS value ≥ median RS value) and low-risk groups (samples with an RS value < the median RS value) according to the median RS value. The prognostic difference between the high- and low-risk groups was evaluated using Kaplan-Meier curves and the significance was calculated using the log-rank test, and the effectiveness of the RS model was estimated by the area under the receiver-operating characteristic curve. In the validation set, the expression level of each mRNA was converted to the same probability distributions as that of the training dataset using Z score transformation, and the prognosis of the samples in the validation set was evaluated using the RS model.
Construction of a nomogram to study the association between independent prognostic factors and survival prognosis
In order to further investigate the association between clinical data and survival prognosis, the mRNAs identified to be significantly associated with prognosis were used to develop a nomogram using RMS package version 5.1–2 in R 3.4.0 (https://cran.r-project.org/web/packages/rms/index.html) (30). The scoring criteria were established according to the regression coefficients of all independent variables. Each value of an independent variable was assigned a score, and a total score was calculated for each sample. The probability of the outcome for each sample was calculated from the total score using a transforming function. The probability evaluation was performed using the nomogram method (31), and the nomogram was used to assess the association between the clinical factors and prognosis.
Screening and pathway analysis of mRNAs associated with prognostic risk
The training dataset samples were divided into high- and low-risk groups according to the RS. The differences between the groups in the mRNA expression matrix of the samples were analyzed using the edgeR package with false discovery rate <0.05 and |log2(fold-change)|>1 applied as thresholds to define significant differences. Pathway enrichment analysis was performed on the mRNAs with significant differential expression between the high- and low-risk groups using the GSEA (32). P<0.05 was selected as the threshold for identification of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways significantly enriched in the DEG set (33).
Results
Identification of mRNAs with significant differential expression between groups with different prognosis
According to the source tissue, the 348 samples in the training set were divided into 311 STAD and 37 control samples, and the differences in the mRNA expression levels between the two groups were analyzed using the edgeR package. A total of 1,597 significantly differentially expressed mRNAs were identified (Fig. 2A). The results of hierarchical clustering analysis revealed a significant difference in the gene expression patterns between the tumor and control samples (Fig. 2B).
Screening for prognosis-associated genes and clinical factors
In the training set, univariate Cox regression analysis was performed on the 1,597 significantly differentially expressed mRNAs, 92 of which were identified to be significantly associated with survival prognosis (P<0.05; data not shown). In addition, the clinical information associated with the samples in the training set was subjected to univariate and multivariate Cox regression analyses; the results demonstrated that age, radiation therapy and recurrence were significantly associated with prognosis and were significant independent prognostic factors (Table II).
Establishment and evaluation of the RS model
Selection of an optimal mRNA combination
The expression matrix of the 92 mRNAs significantly associated with prognosis in the training set was selected as the input, and mRNA combinations were screened for optimal results using the LASSO Cox regression model in the penalized package. In the cyclic execution of the 1,000 CVL algorithm, the maximum CVL value (−730.883) was obtained with λ=21.178 (Fig. 3A and B), and 10 mRNAs were selected based on this parameter: Hemoglobin β (HBB), chromosome 4 open reading frame 48 (C4orf48), mannosidase endo-α-like (MANEAL), C-X-C motif chemokine ligand 3 (CXCL3), tripartite motif-containing 31 (TRIM31), transmembrane protein 200A (TMEM200A), serpin family E member 1 (SERPINE1), coagulation factor V (F5), NADPH oxidase organizer 1 (NOXO1) and Dickkopf WNT signaling pathway inhibitor 1 (DKK1 (Table III; Fig. 3C).
Determination of the mRNA expression cutoff values
For each mRNA included in the optimal mRNA combination, the expression level cut-off value was selected using the X-Tile Software with the Monte-Carlo P<0.05. As presented in Fig. 4, the cut-off values of HBB, C4orf48, DKK1, F5, NOXO1, SERPINE1, CXCL3, TMEM200A, MANEAL and TRIM31 were 6.4, 4.4, 1.6, 3.0, 1.2, 3.8, 5.8, 0.9, 1.4 and 0.9, respectively. Improved survival time was observed in patients with high expression levels of HBB, C4orf48, DKK1, F5, SERPINE1 and TMEM200A compared with patients with high expression levels of these genes, as well as in patients with low expression levels of NOXO1, CXCL3, MANEAL and TRIM31 compared with patients with low expression levels of these genes (Fig. 4).
The RS prediction model was established as follows: RS = 0.27 × status (HBB) + 0.191 × status (C4orf48) + (−0.726) × status (MANEAL) + (−0.240) × status (CXCL3) + (−0.567) × status (TRIM31) + 0.022 × status (TMEM200A) + 0.663 × status (SERPINE1) + 0.429 × status (F5) + (−0.288) × status (NOXO1) + 0.729 × Status (DKK1). The RS prediction model was used to evaluate and verify the risk prediction effect for samples in the training and validation datasets (Fig. 5). According to the median RS value, high- and low-risk stratified analyses of the samples were performed. As exhibited in Table IV, five clinical factors were revealed to be associated with overall survival time according to univariable analysis, including age, pathological T, pathological stage, radiation therapy and recurrence in the low-risk group (P<0.05). Further multivariable Cox regression analysis revealed that radiation therapy was an independent clinical factor associated with STAD prognosis (P=0.035). In the high-risk group, H. pylori infection, pathological T, pathological N, pathological M, pathological stage and tumor grade were significantly associated with overall survival time (P<0.05). Among these factors, pathological N was an independent clinical factor for STAD prognosis (P=0.011).
 | Table IV.Stratified analysis of clinicopathological characteristics in the high- and low-risk groups. |
Association between clinical factors and survival prognosis according to the nomogram analysis
In the training set, three clinical factors (age, radiation therapy and recurrence) were subjected to stratified analysis in order to study the differences between the low- and high-risk groups for each clinical factor (Fig. 6). As shown in Fig. 6, the low-risk group exhibited longer overall survival times than the high-risk group.
In order to further analyze the association between age, radiation treatment, recurrence, and risk score with survival prognosis, a nomogram analysis was performed. Cox regression analysis suggested these four clinical factors were all significantly associated with survival prognosis (P<0.05, Fig. 7A). Then, a nomogram was established to predict the survival time of the samples. According to the nomogram, the 3- and 5- year survival probability may be predicted by matching the clinical indicators to the ‘Total Points’ axis (Fig. 7B).
Pathway analysis of the mRNAs associated with prognosis
The training dataset was subdivided into high- and low-risk groups according to the RS, and the differences in the mRNA expression matrix of the samples between these groups were analyzed using the edgeR package (Fig. 8A). A total of 728 significant DEGs were identified, including 221 downregulated and 507 upregulated DEGs. The samples were sorted according to the cor value and were clustered using the top 100 DEGs (top 50 positive and negative cor values; Fig. 8B).
GSEA pathway enrichment annotation was performed on the DEGs significantly associated with risk factors, and a total of eight significant KEGG pathways were identified (Table V). The heatmap of the genes involved in each pathway and the association between gene expression levels and pathways are presented in Fig. 9.
Discussion
The aberrant expression levels of certain genes are significantly associated with the pathogenesis and prognosis of GC (34). In the present study, a large amount of mRNA expression profiling data and clinical information from patients with STAD documented in TCGA database were used to identify statistically significant DEGs between STAD and healthy tissues. A total of 92 mRNAs significantly associated with survival were obtained by univariate Cox regression analysis.
The risk assessment tools that are based on gene expression levels can identify high-risk populations in relation to a specific disease and may be useful in the subsequent clinical decision-making process for healthcare providers and patients (12). In order to construct a risk assessment tool for the assessment of prognosis in patients with STAD, an optimal mRNA combination was identified among the 92 significant DEGs comprising 10 mRNAs in the present study, which were selected as a prognostic gene signature to create the RS model. The effectiveness of this model was evaluated in the training and validation datasets, and the results suggested that this risk assessment tool was useful for identifying populations with a high risk of developing STAD. To the best of our knowledge, aside from the present study, there is only one published RS model constructed according to gene expression levels, which includes a 53-gene signature and a prognostic scoring system (20). There are two other risk assessment tools that have been developed for the Japanese population, and their risk factors include age, sex, the combination of an anti-H. pylori antibody and serum pepsinogen, HbA1c level, smoking status, family history of GC and consumption of high-salt food (12,18). The risk assessment tool developed in the present study is simple and inexpensive enough to be used both in normal clinical practice and for mass screening.
The results of the present study revealed an improved prognosis for patients with high expression levels of HBB, C4orf48, DKK1, F5, SERPINE1 and TMEM200A and low expression levels of NOXO1, CXCL3, MANEAL and TRIM31. Although there are limited relevant studies on F5 and TMEM200A, certain functions of the remaining genes have been investigated. HBB is a globin protein constituting the most common form of hemoglobin in adult humans, and abnormal expression of HBB can lead to blood diseases, such as hemoglobinopathy and hereditary nigremia (11,35). C4orf48 is a gene identified in the Wolf-Hirschhorn syndrome critical chromosomal region that encodes a putative neuropeptide and is important for development of the neocortex and cerebellar (36) and cell differentiation (37). DKK1 protein is a soluble inhibitor of WNT that serves important roles in skeletal development (38) and is associated with the presence of lytic bone lesions in patients with multiple myeloma (39). SERPINE1, also known as plasminogen activator inhibitor type 1, is a member of the serine protease inhibitor family and is the major physiological regulator of the urokinase-type plasminogen activator-dependent pericellular plasmin-generating cascade (40,41). SERPINE1 has also been reported to serve roles in in acute lymphoblastic leukemia (42) and keratinocyte migration (43).
With the exception of MANEAL, which may be involved in neurological disorders (44), the other three genes with high expression levels in the samples with good prognosis are associated with cancer, particularly NOXO1 and TRIM31 (45–49). NOXO1 can be induced in tumor epithelial cells and serves an important role in tumorigenicity and the tumor-initiating property of GC cells (46). In addition, NOXO1 may affect colon epithelium homeostasis and prevent inflammation (45). Previous studies have demonstrated that CXCL3 may be a biomarker of breast and prostate cancer (47,49). TRIM31, which is a ring finger, B-box and coiled-coil protein upregulated in GC cells and a potential biomarker of GC, can inhibit cell proliferation (48), and its cellular level may be regulated by a number of mechanisms, including the ubiquitin-proteasome system (50). GSEA pathway enrichment annotation revealed that eight pathways were enriched in the DEGs significantly associated with the risk factors, such as the ‘adherens junction’, ‘TGF-β signaling pathway’, ‘Wnt signaling pathway’, ‘JAK-STAT signaling pathway’, ‘MAPK signaling pathway’, ‘mTOR signaling pathway’ and ‘pathways in cancer’, all of which serve substantial roles in human carcinogenesis (51–54). The functions of these prognostic genes are different compared with those of the genes identified in a previous study, which were associated with the cell cycle, RNA/non-coding RNA processes, acetylation and extracellular-matrix organization (20).
Independent validation of two different datasets and previous studies indicate that the RS model developed in the present study may be effective. However, a limitation of the present study was that it was an extensive bioinformatics analysis based on published data; the results should be validated using in vitro or in vivo models. However, the results of the present study may help other investigators to conduct relevant research.
In conclusion, a risk assessment tool for assessing the prognosis of patients with STAD was developed and validated in the present study. The 10 identified prognostic mRNAs were associated with several cellular processes and signaling pathways, such as the ‘adherens junction’, TGF-β signaling pathway’, ‘Wnt signaling pathway’, ‘JAK-STAT signaling pathway’, ‘MAPK signaling pathway’, ‘mTOR signaling pathway’ and ‘pathways in cancer’, and may be recommended as promising prognostic biomarkers or a prognostic signature of STAD. The present risk assessment tool may help identify patients with a high risk of STAD, and the proposed prognostic mRNAs may help elucidate the pathogenesis of STAD.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
ZL designed the present study. EG and FT conducted the bioinformatics analysis. EG contributed to writing the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
CVL |
cross-validation likelihood |
|
DEG |
differentially expressed gene |
|
GC |
gastric cancer |
|
GEO |
Gene Expression Omnibus |
|
GSEA |
Gene Set Enrichment Analysis |
|
KEGG |
Kyoto Encyclopedia of Genes and Genomes |
|
RNA-seq |
high-throughput RNA sequencing |
|
RS |
risk score |
|
STAD |
stomach adenocarcinoma |
|
TCGA |
The Cancer Genome Atlas |
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