Construction and analysis of a reliable five-gene prognostic signature for colon adenocarcinoma associated with the wild-type allelic state of the COL6A6 gene.

ABSTRACT

Background: Tumors emerge by acquiring a number of mutations over time. The first mutation provides a selective growth advantage compared to adjacent epithelial cells, allowing the cell to create a clone that can outgrow the cells that surround it. Subsequent mutations determine the risk of the tumor progressing to metastatic cancer. Some secondary mutations may inhibit the aggressiveness of the tumor while still increasing the survival of the clone. Meaningful mutations in genes may provide a strong molecular foundation for developing novel therapeutic strategies for cancer. Methods: The somatic mutation and prognosis in colon adenocarcinoma (COAD) were analyzed. The copy number variation (CNV) and differentially expressed genes (DEGs) between the collagen type VI alpha 6 chain (COL6A6) mutation (COL6A6-MUT) and the COL6A6 wild-type (COL6A6-WT) subgroups were evaluated. The independent prognostic signatures based on COL6A6-allelic state were determined to construct a Cox model. The biological characteristics and the immune microenvironment between the two risk groups were compared. Results: COL6A6 was found to be highly mutated in COAD at a frequency of 9%. Patients with COL6A6-MUT had a good overall survival (OS) compared to those with COL6A6-WT, who had a different CNV pattern. Significant differences in gene expression were established for 593 genes between the COL6A6-MUT and COL6A6-WT samples. Among them, MUC16, ASNSP1, PRR18, PEG10, and RPL26P8 were determined to be independent prognostic factors. The internally validated prognostic risk model, constructed using these five genes, demonstrated its value by revealing a significant difference in patient prognosis between the high-risk and low-risk groups. Specifically, patients in the high-risk group exhibited a considerably worse prognosis than did those in the low-risk group. The high-risk group had a significantly higher proportion of patients over 60 years of age and patients in stage III. Moreover, the tumor immune dysfunction and exclusion (TIDE) score and the expression of human leukocyte antigen (HLA) family genes were all higher in the high-risk group than that in the low-risk group. Conclusions: The allelic state of COL6A6 and the five associated DEGs were identified as novel biomarkers for the diagnosis and prognosis of COAD and may be therapeutic targets in COAD.