The KRAS-G12D mutation drives venous thromboembolism (VTE) and colorectal cancer progression via MAPK/ERK signaling.

[OBJECTIVE] KRAS mutations occur in nearly 50 % of colorectal cancer (CRC) cases, with G12D representing the most frequent variant. While CRC is recognized as a moderate risk factor for venous thromboembolism (VTE), the thrombogenic potential of KRAS-G12D mutations remains poorly understood.

[METHODS] We established a KRAS-G12D-associated coagulation gene (KMCG) prognostic model through integrative analysis of clinical data from CRC patients. Mechanistic investigations combining in vitro and in vivo models revealed that KRAS-G12D potentiates thrombotic risk through MAPK/ERK pathway activation.

[RESULTS] Integrating TCGA data, we constructed a KRAS-G12D-associated coagulation gene (PLCG2/MAPK12/C4B)-based prognostic model, where high-risk patients exhibited significantly reduced overall survival (HR=3.44) and superior 1-year AUC (0.718). Mechanistic profiling revealed high-risk enrichment in coagulation cascades, MAPK signaling, and immune infiltration, coupled with elevated tumor mutational burden (TMB) and immunotherapy sensitivity. Clinical validation confirmed KRAS-G12D mutation markedly increased D-dimer levelsand VTE incidence. Functional studies demonstrated mutant-driven platelet hyperactivation via MAPK/ERK pathway activation, evidenced by elevated aggregation rates and procoagulant endothelial transformation. In vivo, MAPK/ERK inhibitor U0126 attenuated thrombosis and metastasis, validating the pathway's dual role in thrombogenesis and tumor progression.

[CONCLUSION] Our findings establish KMCG as a novel biomarker integrating thrombotic risk and tumor progression, while mechanistically linking KRAS-G12D-driven MAPK activation to both cancer metastasis and thrombosis. This dual regulatory axis provides therapeutic targets for simultaneously managing thrombotic complications and malignant progression in KRAS-mutant CRC.