Colorectal cancer (CRC) is the third most common type of cancer in Europe [1], after breast and prostate cancer, and it’s the second top cause of cancer deaths in the U.S [2].
Cancer increases the risk of developing a hypercoagulable state, leading to venous thromboembolism (VTE), such as deep vein thrombosis (DVT) or pulmonary embolism (PE), with this risk further amplified by cancer treatments [1]. VTE is notably prevalent in CRC patients, with a cumulative incidence as high as 8.9%, significantly impacting morbidity and mortality [3]. Managing VTE in CRC is complex due to its rising incidence, high risk of recurrence, and the complications associated with bleeding from anticoagulation therapy [1].
Risk stratification is crucial in determining when to start thromboprophylaxis in CRC patients and relies on the calculation of specific risk scores [3].
A retrospective study was conducted to explore the connection between VTE risk and KRAS-activating mutations in CRC, identifying a potential new risk factor for VTE that could inform the enhancement of thromboprophylaxis protocols [3].
VTE risk stratification and oncogenes
Stratifying the risk of thrombosis in the context of cancer, a heterogeneous disease with varied risk factors including subtype, histology, location, grade, stage, and diagnosis duration, is challenging due to the multitude of considerations. To address this, several risk stratification models, such as the well-validated Khorana score, have been developed, utilizing clinical and laboratory characteristics to assess risk effectively [3].
The advent of routine molecular testing for tumor and blood samples has expanded cancer classification beyond just histological type and location, raising the question of the impact of tumor genetics, including specific mutations, on thrombotic risk [3].
Several studies have delved deeper into the topic of oncogene-associated thrombosis, with some focusing on the potential involvement of KRAS gene mutations [3].
The KRAS gene, a member of the RAS gene family linked to human tumor development, is pivotal in regulating cell proliferation, differentiation, and survival through its molecular switch mechanism. Mutations in KRAS fix the protein in an active “on” state, enhancing downstream signaling that promotes cell growth and contributes to tumor formation [3]. Notably, KRAS mutations are prevalent in tumorigenesis, affecting about 42–52% of colorectal cancer (CRC) patients [4].
The association between KRAS mutation and heightened thrombosis risk may be tied to the fundamental mechanisms underlying cancer-associated thrombosis [3].
Numerous studies have established the role of heparanase, an enzyme whose imbalanced degradation of heparin contributes to hypercoagulability, in cancer-associated thrombosis (CAT) [5]. These studies consistently demonstrate that the expression of heparanase is linked to the expression of oncogenes, notably including KRAS mutations [3].
An additional connection between thrombosis risk and KRAS mutations may be found in tissue factor (TF), a key player in cancer-associated thrombosis. CRC amplifies the clotting system’s activation, particularly through the upregulation of certain coagulation proteins such as TF, which is notably overexpressed in malignant cells harboring KRAS mutations [1-6].
The study
This retrospective study assessed the Khorana score in 130 CRC patients (46.2% male; 53.8% female) with an average age of 67.3 years. Among them, 109 (83.8%) were classified as low risk for CAT with a Khorana score of <2, while 21 (16.2%) were considered high risk with a score of ≥2. Furthermore, 45 patients (34.6%) developed VTE, including 30 (23.07%) with DVT and 15 (11.53%) with PE [3].
The study findings indicated that the median time for VTE development in the cohort was 48.2 months, with KRAS mutant patients (33.1%) experiencing a median VTE onset at 12 months, while the median time for KRAS wild-type patients (66.9%) had not yet been reached. Additionally, at 9 months, 26.5% of KRAS mutant patients had developed VTE, compared to only 8.4% of KRAS wild-type patients. This disparity widened by 24 months, where 66.4% of KRAS mutant patients had VTE, significantly higher than the 22.1% observed in KRAS wild-type patients, highlighting a more rapid increase in VTE development among those with KRAS mutations [3].
Furthermore, the authors highlighted a statistically significant association between KRAS mutations and an elevated risk of thrombosis, with an odds ratio (OR) of 2.758 for VTE overall. Specifically, the ORs were 3.125 for DVT and 1.752 for PE, affirming the significant impact of KRAS mutations on the risk of thrombotic events [3].
Limitations and conclusions
Identifying CRC patients at high risk of thrombosis is essential, given their increased risk of rectal bleeding, anemia, and VTE, to improve thromboprophylaxis decisions and patient care outcomes [3].
The study’s findings reveal that the incidence of VTE is 2.75 times higher in patients with mutant KRAS than in those with wild-type KRAS. This indicates that the activating KRAS mutation serves as an independent risk factor for VTE and could play a significant role in VTE risk stratification models [3].
Moreover, the statistical analysis reveals that the KRAS mutation significantly influences the risk of thrombosis, especially in the subgroup with a low Khorana score. This suggests its potential as a predictive marker in the absence of other thrombosis risk factors [3].
Despite this, further research is necessary to better understand the impact of KRAS mutations on VTE, focusing on mechanisms such as heparanase production and TF overexpression, with the goal of developing enhanced VTE risk stratification models that incorporate genetic markers [3].
References
- PA Rees, HW Clouston, S Duff, CC Kirwan, Colorectal cancer and thrombosis, International journal of colorectal disease, (2018);33(1):105-108, doi: 10.1007/s00384-017-2909-2
- RL Siegel, NS Wagle, A Cercek, RA Smith, A Jemal, Colorectal cancer statistics, 2023, CA: a cancer journal for clinicians, (2023);73(3):233-254, doi: 10.3322/caac.21772
- RA Emiliescu, M Jinga, HT Cotan, AM Popa, CM Orlov-Slavu, MC Olaru, CI Iaciu, AI Parosanu, M Moscalu, C Nitipir, The role of KRAS Mutation in Colorectal Cancer-Associated Thrombosis, International journal of molecular sciences, (2023);24(23):16930, doi: 10.3390/ijms242316930
- M Meng, K Zhong, T Jiang, Z Liu, HY Kwan, T Su, The current understanding on the impct of KRAS on colorectal cancer, Biomedicine & pharmacotherapy, (2021);140:111717, doi: 1016/j.biopha.2021.111717
- NJ Nasser, J Fox, A Agbarya, Potential Mechanisms of Cancer-Related Hypercoagulability, Cancers, (2020);12(3):566, doi: 10.3390/cancers12030566
- JL Yu, L May, V Lhotak, S Shahrzad, S Shirasawa, JI Weitz, BL Coomber, N Mackman, JW Rak, Oncogenic events regulate tissue factor expression in colorectal cells: implications for tumor progression and angiogenesis, Blood, (2005);105(4):1734-41, doi: 10.1182/blood-2004-05-2042