Abstract
Background: Colon cancer (COAD) has been identified as being among the most prevalent tumors globally and ranked the third major contributor to cancer-related mortality. COAD is a molecularly heterogeneous disease. There are great differences in clinical manifestations and prognosis among different molecular subtypes. Methods:379 TCGA-COAD samples were divided into four subtypes: primary proliferative, with collective, crypt-like, and EMT invasion. The differences among the four subtypes were analyzed from the multidimensional perspectives of immunity, genomic variation, and prognosis. The limma package was utilized to identify differentially expressed genes (DEGs) amongst different molecular subtypes. Phenotype-related coexpressed gene modules were identified using WGCNA. The polygenic prognosis model was created utilizing the lasso Cox analysis and verified by time-dependent subject operating characteristics (ROC). Results: There are some differences in prognosis, TMB and common gene variation, immune score, and immunotherapy/chemotherapy between proliferative and three invasive molecular subtypes. 846 differential genes (DEGs) were obtained by limma packet analysis. Differential gene analysis was utilized to screen the DEGs among distinct subtypes, which were significantly enriched in the pathways related to tumorigenesis and development. Co-expression network analysis found 46 co-expressed genes correlated with proliferative and three invasive phenotypes. Based on differentially co-expressed genes, we developed a prognostic risk model of 8-genes signature, which exhibited strong stability regardless of external and internal validation. RT-PCR experiments proved the expression of eight genes in tumor and normal samples. Conclusion: We have developed an eight-gene signature prognostic stratification system. Furthermore, we proposed that this classifier can serve as a molecular diagnostic tool to assess the prognosis of colon cancer patients.
Highlights
Colon cancer is extensively recognized to be among the most prevalent tumors globally and has been ranked as the third major contributor to cancer mortality (Labianca et al, 2010)
The subtypes of TCGACOAD were screened from the Supplementary Materials studied by Shaying Zhao et al (Wang et al, 2018), after deleting redundant samples through the sample information in the ‘case’ column, a total of 366 samples were divided into four subtypes, of which 155 samples were collective subtypes, 76 samples were crypt-like subtypes, 62 samples were epithelialmesenchymal transformation (EMT) subtypes, and 73 samples were identified as proliferative subtypes
Among the three invasive molecular subtypes, EMT and CryptLike subtypes have the worst prognosis, and Collective has the best prognosis; we evaluated the correlation between the four subtypes and PFS and found the same findings, that is, EMT and CryptLike subtypes exhibited the most unfavorable prognosis, and Collective exhibited favorable prognosis (Figure 1B); we analyzed the relationship with DSS
Summary
Colon cancer is extensively recognized to be among the most prevalent tumors globally and has been ranked as the third major contributor to cancer mortality (Labianca et al, 2010). The survival rate of COAD patients has been improved with the increase of treatment methods, the prognosis is still very poor (Neri et al, 2010; Roncucci and Mariani, 2015).In addition to targeted therapy, immunotherapy seems to be a promising treatment for advanced CRC. The proportion of DMMR/MSI-H in metastatic colon cancer is only about 5% (Jung et al, 2020), and the effective rate in such patients is only 30–40% (Le et al, 2017), which indicates that there are some limitations in the application of MSI status as an immune checkpoint inhibitor. Colon cancer (COAD) has been identified as being among the most prevalent tumors globally and ranked the third major contributor to cancer-related mortality. There are great differences in clinical manifestations and prognosis among different molecular subtypes
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