Progressively altered genes in colorectal carcinogenesis link oncogenesis immune cycle and tumor microenvironment

The adenoma-adenocarcinoma pathway represents a crucial mechanism underlying the development of colorectal precancerous lesions, encompassing approximately 85%-90% of colorectal cancer (CRC). Elucidating the molecular mechanisms underlying colorectal cancer progression is of paramount importance for achieving early and accurate diagnosis as well as effective treatment. We collected peripheral blood mononuclear cells (PBMC) from healthy controls, adenoma patients, and adenocarcinoma patients, and performed transcriptomic profiling to characterize dynamic gene expression during carcinogenesis. Diagnostic potential was assessed using receiver operating characteristic (ROC) analysis, and a random-forest model was trained to classify disease status. The screening identified genes with consistent expression changes as potential early diagnostic markers, and further exploration of their functions and significance in CRC is conducted through analysis of the TCGA database. The findings revealed that the progression of precancerous lesions in the "Normal-Adenoma-Cancer" (N-A-C) sequence was accompanied by a sustained enhancement of the immune response. Notably, HECW2, WARS1, SLC16A3, SECTM1, IFITM3, ADAMTSL4, FCGR1A, F2RL1, OPLAH, SERPINA1, FCGR1CP showed consistent upregulation with promising diagnostic performance. In our PBMC cohort, the random-forest classifier achieved an accuracy of 93.62%, indicating potential for distinguishing cancer from precancerous lesions. The bioinformatics analysis revealed a significant association of these genes with DNA methyltransferase, DNA mismatch repair, m6A regulator, tumor mutational burden (TMB) and microsatellite instability (MSI). Furthermore, a detailed analysis was further performed on WARS1. In the "N-A-C" sequence, WARS1 exhibited a significant upregulation in both blood and tissues, demonstrating a positive correlation with augmented infiltration of immune cells, activation of stromal and immune responses, as well as heightened activity during the cancer immune cycle. However, it demonstrates a declining trend in the progression of CRC from stage I to IV, which may be intricately associated with the metastasis of CRC. The WARS1 can serve as a reliable indicator of the immune response in CRC, thereby demonstrating its potential to impede tumorigenesis or metastasis.