Comparison of the differentially enriched mutations/pathways between stage II and stage IV dMMR/MSI-H colorectal cancer

Objective Colorectal cancer (CRC) patients with high microsatellite instability (MSI-H) and mismatch repair deficiency (dMMR) had heterogeneous pathology and distinct prognoses. This study aimed to examine the difference in the gene expression profile of dMMR/MSI-H CRC patients with different disease stages and explore the different molecular mechanisms of disease progression. Methods A total of 47 patients with dMMR/MSI-H CRC were enrolled and retrospectively studied, including 27 stage II and 20 stage IV patients. Each patient had paired tumor tissue and white blood cell samples, which were analyzed by next-generation sequencing (NGS) of 416 cancer-relevant genes. Pathway enrichment analysis was then performed to analyze the disease stage-specific signaling pathways. Results A total of 2878 mutation sites, spanning 378 mutated genes, were detected from the 47 dMMR/MSI-H CRC patients. The mutation frequencies of SMARCA4, EPHA3, MTHFR, RAD50, and PDGFRB were significantly higher in stage II patients than in stage IV patients ( p < 0.05), whereas the stage II patients had significantly lower mutation frequencies of TSC2, FGFR1, PTPN13, SMAD3, and STK11 than stage IV patients ( p < 0.05). Sixty-three mutated genes were unique to stage II tumors, while 36 mutated genes were exclusively present in stage IV tumors. Pathway analyses demonstrated the PI3K-AKT pathway was shared by both stage II and stage IV tumors, whereas multiple other signaling pathways showed disease stage-specific enrichment. Conclusion There were profound differences in mutational profile and molecular mechanisms between stage II and stage IV dMMR/MSI-H CRC.