KRAS, APC, and TP53 mutations define opposing immune archetypes in stage III colorectal cancer

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Abstract
Colorectal cancer (CRC) exhibits marked genomic and immune heterogeneity; stage III CRC remains prone to recurrence and metastasis despite standard therapy. To delineate genotype–immune relationships, we integrated whole-exome sequencing and transcriptomic profiling in 69 Thai patients with stage III CRC. We investigated the top 3 somatic mutations and their effects on the tumor immune microenvironment. Our analysis identified TP53 , APC , and KRAS as the most frequently mutated genes, each associated with distinct immune phenotypes. We observed a clear dichotomy: APC and TP53 mutations correlated with an immune-depleted, exclusionary phenotype, whereas activating KRAS mutations were linked to a pro-inflammatory, myeloid-rich microenvironment. In tumors harboring co-mutations, the KRAS -associated inflammatory signature predominated and correlated with a trend toward poorer overall survival (hazard ratio = 17.4, 95% CI: 1.8–170.8, P = 0.014). KRAS co-occurrence with TP53 retained the inflammatory signature and similarly correlated with a trend toward poorer overall survival (hazard ratio = 10.6, 95% CI: 1.2–91.2, P = 0.032). These findings indicate that CRC evolution establishes predictable, genotype-specific immune archetypes that distinguish immune-depleted from dysfunctional inflamed tumors. This framework may serve as a biomarker to stratify patients and guide tailored immunotherapy strategies for stage III CRC.

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