Abstract
The role of an extracellular matrix- (ECM-) receptor interaction signature has not been fully clarified in gastric cancer. This study performed comprehensive analyses on the differentially expressed ECM-related genes, clinicopathologic features, and prognostic application in gastric cancer. The differentially expressed genes between tumorous and matched normal tissues in The Cancer Genome Atlas (TCGA) and validation cohorts were identified by a paired t-test. Consensus clusters were built to find the correlation between clinicopathologic features and subclusters. Then, the least absolute shrinkage and selection operator (lasso) method was used to construct a risk score model. Correlation analyses were made to reveal the relation between risk score-stratified subgroups and clinicopathologic features or significant signatures. In TCGA (26 pairs) and validation cohort (134 pairs), 25 ECM-related genes were significantly highly expressed and 11 genes were downexpressed in gastric cancer. ECM-based subclusters were slightly related to clinicopathologic features. We constructed a risk score model = 0.081∗log2 (CD36) + 0.043∗log2 (COL5A2) + 0.001∗log2 (ITGB5) + 0.039∗log2 (SDC2) + 0.135∗log2 (SV2B) + 0.012∗log2 (THBS1) + 0.068∗log2 (VTN) + 0.023∗log2 (VWF). The risk score model could well predict the outcome of patients with gastric cancer in both training (n = 351, HR: 1.807, 95% CI: 1.292-2.528, P = 0.00046) and validation (n = 300, HR: 1.866, 95% CI: 1.347-2.584, P = 0.00014) cohorts. Besides, risk score-based subgroups were associated with angiogenesis, cell adhesion molecules, complement and coagulation cascades, TGF-beta signaling, and mismatch repair-relevant signatures (P < 0.0001). By univariate (1.845, 95% CI: 1.382-2.462, P < 0.001) and multivariate (1.756, 95% CI: 1.284-2.402, P < 0.001) analyses, we regarded the risk score as an independent risk factor in gastric cancer. Our findings revealed that ECM compositions became accomplices in the tumorigenesis, progression, and poor survival of gastric cancer.
Highlights
As a common tumor of the digestive system, gastric cancer is the fifth common malignant tumor and the third leading cause of cancer death in the world [1, 2]
The expressions of AGRN, CD47, COL11A1, COL1A2, COL3A1, COL4A1, COL4A2, COL5A1, COL5A2, COL5A3, COL6A3, COMP, DAG1, HMMR, ITGA2, ITGA4, ITGAV, ITGB8, LAMB1, LAMB3, LAMC2, SPP1, THBS2, VWF, and SDC1 were significantly highly expressed in gastric cancer, while 11 genes CD36, CHAD, COL4A6, ITGA8, ITGA9, LAMA2, RELN, SV2C, TNXB, LAMB4, and LAMC3 were downexpressed in tumorous tissues (Figure 1(b) and Supplementary Figure 2)
Through the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we systematically examined 84 extracellular matrix (ECM)-receptor interactionrelevant genes in this study and found that most of them were differentially expressed in gastric cancer tissues
Summary
As a common tumor of the digestive system, gastric cancer is the fifth common malignant tumor and the third leading cause of cancer death in the world [1, 2]. ECM constitutes the main part of the extracellular microenvironment [4]. It is a complex organic unity constructed by a variety of insoluble extracellular macromolecules in a certain proportion and structure. It is the site of cell survival and activity, with physical functions such as connection, support, water retention, pressure resistance, and protection.
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