Abstract
The overall survival of metastatic colon adenocarcinoma (COAD) remains poor, so it is important to explore the mechanisms of metastasis and invasion. This study aimed to identify invasion-related genetic markers for prognosis prediction in patients with COAD. Three molecular subtypes (C1, C2, and C3) were obtained based on 97 metastasis-related genes in 365 COAD samples from The Cancer Genome Atlas (TCGA). A total of 983 differentially expressed genes (DEGs) were identified among the different subtypes by using the limma package. A 6-gene signature (ITLN1, HOXD9, TSPAN11, GPRC5B, TIMP1, and CXCL13) was constructed via Lasso-Cox analysis. The signature showed strong robustness and could be used in the training, testing, and external validation (GSE17537) cohorts with stable predictive efficiency. Compared with other published signatures, our model showed better performance in predicting outcomes. Pan-cancer expression analysis results showed that ITLN1, TSPAN11, CXCL13, and GPRC5B were downregulated and TIMP1 was upregulated in most tumor samples, including COAD, which was consistent with the results of the TCGA and GEO cohorts. Western blot analysis and immunohistochemistry were performed to validate protein expression. Tumor immune infiltration analysis results showed that TSPAN11, GPRC5B, TIMP1, and CXCL13 protein levels were significantly positively correlated with CD4+ T cells, macrophages, neutrophils, and dendritic cells. Further, the TIMP1 and CXCL13 proteins were significantly related to the tumor immune infiltration of CD8+ T cells. We recommend using our signature as a molecular prognostic classifier to assess the prognostic risk of patients with COAD.
Highlights
Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the fourth leading cause of cancer-related death worldwide, with more than 2.2 million new cases and 1.1 million related deaths predicted by 2030 [1]
Identification of molecular subtypes based on NMF We designed a protocol (Fig. 1) to analyze the invasionrelated genes associated with the prognosis of colon carcinoma
Correlations between gene expression and tumor immune cell infiltration The results showed that the expression levels of the GPRC5B, Tissue inhibitor of metalloproteinase 1 (TIMP1), and TSPAN1 genes were significantly positively correlated with CD4+ T cells, macrophages, neutrophils, and dendritic cells
Summary
Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the fourth leading cause of cancer-related death worldwide, with more than 2.2 million new cases and 1.1 million related deaths predicted by 2030 [1]. About 20% of CRC patients have metastatic disease when first diagnosed, and about 30–50% of patients with primary colon cancer relapse and die from metastatic cancer [2, 3]. Metastasis is a major cause of death in cancer patients. Metastasis requires cancer cells to leave the primary tumor and acquire the ability to migrate and invade. Understanding the mechanisms involved in cell invasion and migration in complex environments is a critical step in successful anti-metastasis therapy. The process of epithelial-mesenchymal transition has been found
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