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

IF 5 2区医学 Q2 Medicine

Translational Oncology Pub Date : 2025-09-18 DOI:10.1016/j.tranon.2025.102529

Jieqi Mao , Xu Ming , Mei Wang , Yichao Du , Yang Shen , Dapeng Li , Ziyan Zhu , Xu Li , Jikun Li

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引用次数: 0

Abstract

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.

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KRAS-G12D突变通过MAPK/ERK信号传导驱动静脉血栓栓塞（VTE）和结直肠癌的进展。

目的：KRAS突变发生在近50%的结直肠癌（CRC）病例中，其中G12D是最常见的突变。虽然CRC被认为是静脉血栓栓塞（VTE）的中度危险因素，但KRAS-G12D突变的血栓形成潜力仍然知之甚少。方法：通过对结直肠癌患者临床资料的综合分析，建立kras - g12d相关凝血基因（KMCG）预后模型。结合体外和体内模型的机制研究表明，KRAS-G12D通过激活MAPK/ERK途径增强血栓形成风险。结果：整合TCGA数据，我们构建了基于kras - g12d相关凝血基因（PLCG2/MAPK12/C4B）的预后模型，其中高危患者的总生存率显著降低（HR=3.44）， 1年AUC较优（0.718）。机制分析显示凝血级联、MAPK信号和免疫浸润的高危富集，以及肿瘤突变负担（TMB）和免疫治疗敏感性的升高。临床验证证实KRAS-G12D突变显著增加d -二聚体水平和静脉血栓栓塞发生率。功能研究表明，突变驱动的血小板过度激活通过MAPK/ERK途径激活，证明了聚集率升高和促凝内皮转化。在体内，MAPK/ERK抑制剂U0126减轻了血栓形成和转移，验证了该途径在血栓形成和肿瘤进展中的双重作用。结论：我们的研究结果表明，KMCG是一种整合血栓形成风险和肿瘤进展的新型生物标志物，同时将kras - g12d驱动的MAPK激活与癌症转移和血栓形成联系起来。这种双重调节轴为同时控制kras突变型CRC的血栓并发症和恶性进展提供了治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.