Cancer and thrombosis are associated with a vicious cycle in which cancer can amplify the risk of thrombosis, and thrombosis can amplify the risk of cancer progression. The risk of developing venous thromboembolism (VTE) is higher in cancer patients, and mortality is increased in cancer patients who had VTE compared to those without VTE [1].
The origin of cancer-associated thrombosis (CAT) is multi-factorial, but not random. Specific thrombosis patterns suggest a relationship of causality between specific drivers and thrombosis development.
Cancer types can be grouped into three VTE risk categories:
- High-risk cancers: pancreatic, ovarian, brain, stomach, gynecologic and hematologic
- Intermediate-risk cancers: colon and lung
- Low-risk cancer: breast, prostate and skin
The existence of these three categories suggests a role for specific molecular mechanisms that are characteristic of cancer cells, and which influence the vasculature components, their biology and the tumor microenvironment [2].
Oncogenes
VTE development in cancer is associated with genetic variation in the tumor and the patient.
In patients, deficiencies in antithrombin, protein C and protein S (the three main natural coagulation inhibitors essential for thrombus formation prevention) increase the risk of VTE. Rare mutations or single nucleotide polymorphisms (SNPs) in SERPINC1, PROC and PROS1 genes, encoding for antithrombin, protein C and protein S, respectively, are responsible for these deficiencies.
A good genomic predictor of VTE is the factor V Leiden (FVL) SNP, a mutation in F5 (F5-rs6025, R506Q), which makes the FV protein resistant to inactivation by activated protein C. FVL increases the VTE risk three-fold in European individuals, in whom FVL has a 5% prevalence [3]. In the observational Vienna Cancer and Thrombosis Study, 7.3% of the study cohort presented FVL mutations, including 982 cancer patients with several different malignancies. In this study, 13.9% of patients with FVL developed VTE, compared with 7.6% of patients who did not carry the mutation [4].
SNPs related to VTE have also been found in genes not directly involved in the coagulation cascade. For example, in colorectal cancer patients, three germline SNPs were identified in the ITGB3 gene, expressed by platelets and endothelial cells, and encoding for the beta3 integrin. The exact role of these mutations in platelets and endothelial function is yet to be clarified [3].
In tumor cells, oncogene mutations such as TP53, RAS and EGFR impact the secretome, and thus influence the tumor microenvironment and vasculature. For example, KRAS modulates crucial angiogenic mediators (e.g., VEGF or thrombospondin), affecting immune response, inflammatory cell recruitment, cell growth and CAT [1]. A retrospective cohort study showed that 32.3% of patients with KRAS mutation and colon cancer developed VTE, compared with 17.8% of colon cancer patients with wild-type KRAS [4].
In glioblastoma, EGFR and PTEN alterations are very common and are two important oncogenic drivers in CAT. The overexpression of EGFR or its mutation, EGFRνII (by which EGFR is constitutively active), leads to tissue factor (TF) overexpression and AP-1 activation (an activator of TF). PTEN is an important inhibitor of AP-1, but its loss, combined with EGFR amplification or mutation, exacerbates even more expression of TF [6].
The IDH1/2 mutation status is inversely linked with VTE in patients with glioma. Gliomas are one of the most ‘at-risk’ cancers for VTE. Somatic point mutations of IDH1/2 occur in a large subset of gliomas, most of which are low grade. A study analyzing a discovery cohort of 169 World Health Organization (WHO) grade II–IV gliomas found a relationship between mutant IDH1/2 and reduced TF expression, impaired platelet activity and absence of microthrombi. Microthrombi occurred in 85–90% of wild-type gliomas versus 2–6% of IDH1 mutant gliomas, and mutations in IDH1 reduce VTE occurrence. In fact, VTE did not occur in any of the patients with IDH1 mutated gliomas but occurred in 26–30% of patients with wild-type IDH1 gliomas [7]. Mutant IDH1 has potent antithrombotic activity within gliomas and throughout the peripheral circulation.
Epigenetics
An altered transcriptome can derive from genetic and epigenetic alterations. Epigenetic alteration includes DNA methylation, histone, chromatin modification, post-translational modifications and miRNA effects on gene expression.
miRNAs regulate the expression of several hemostatic factors, both procoagulant and anticoagulant, and the plasminogen activator inhibitor-1 (PAI-1), the main modulator of fibrinolysis [8]. miRNAs can also affect platelet activation and aggregation, and their expression is dysregulated in venous thrombosis, and miRNAs show a differential expression in CAT.
Analyzing plasma from four lung cancer patients with CAT and comparing it with plasma from 12 lung cancer patients who did not develop CAT during follow-up, 14 miRNAs were found to be regulated in a different way: let-7e-5p, let-7g-5p, let-7i-5p, miR-17-5p, miR-30a-5p, miR-125a-5p, miR-125b-5p, miR-140-3p, miR-186-5p, miR-205-5p, miR-301a-3p, miR-363-3p, miR-328-3p and miR-382-5 [9].
Several other miRNAs have also been implicated in TF control, including miR-19b, miR-19a, miR-20a, miR-93, miR-106b, miR-223 and miR-145 [2].
Epigenetic factors other than miRNA are also implicated in CAT development. Clear cell ovarian cancer cells produced FVII protein and released it in complexes, with TF as cargo in microvesicles. This mechanism is implicated in CAT development, and it is driven by hypoxia-induced histone deacetylation, within the promoter region of the FVII gene [10].
However, the relationship between coagulome and epigenetic alteration is reciprocal. Cancer cell treatment with antibodies directed against TF inhibits tumor progression while changing the tumor’s miRNA expression [11].
Summary
Genetic and epigenetic alterations influence the development of CAT. Patients with cancer generally have a hypercoagulable state, caused by genetic alterations that can be further exacerbated by cancer treatment. Genetic alterations in the tumor itself may also contribute to a hypercoagulable state and modulate CAT development. Mutations in PTEN and KRAS predispose to CAT, while mutations in IDH1/2 are inversely correlated with CAT in patients with glioma. Epigenetics mechanism can further increase the risk of CAT.
References
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- Tawil N, Spinelli C, Bassawon R, Rak J. Genetic and epigenetic regulation of cancer coagulome – lessons from heterogeneity of cancer cell populations. Thromb Res. 2020;191 Suppl 1:S99-S105.
- Buijs JT, Versteeg HH. Genes and proteins associated with the risk for cancer-associated thrombosis. Thromb Res. 2020;191 Suppl 1:S43-S49.
- Pabinger I, Ay C, Dunkler D, et al. Factor V Leiden mutation increases the risk for venous thromboembolism in cancer patients – results from the Vienna Cancer And Thrombosis Study (CATS). J Thromb Haemost. 2015;13(1):17-22.
- Ades S, Kumar S, Alam M, et al. Tumor oncogene (KRAS) status and risk of venous thrombosis in patients with metastatic colorectal cancer. J Thromb Haemost. 2015;13(6):998-1003.
- Rong Y, Belozerov VE, Tucker-Burden C, et al. Epidermal growth factor receptor and PTEN modulate tissue factor expression in glioblastoma through JunD/activator protein-1 transcriptional activity. Cancer Res. 2009;69(6):2540-2549.
- Unruh D, Schwarze SR, Khoury L, et al. Mutant IDH1 and thrombosis in gliomas. Acta Neuropathol. 2016;132(6):917-930.
- Morelli VM, Brækkan SK, Hansen JB. Role of microRNAs in Venous Thromboembolism. Int J Mol Sci. 2020;21(7):2602. Published 2020 Apr 9.
- Oto J, Fernández-Pardo A, Plana E, et al. Role of microRNAs in venous thromboembolic disease of patients with lung cancer. Pract. Thromb. Haemost. 3 Suppl 1 (2019) 723 (PB1048).
- Koizume S, Miyagi Y. Potential Coagulation Factor-Driven Pro-Inflammatory Responses in Ovarian Cancer Tissues Associated with Insufficient O₂ and Plasma Supply. Int J Mol Sci. 2017;18(4):809. Published 2017 Apr 12.
- D’Asti E, Anderson GM, Rak J. Inhibition of tissue factor signaling in breast tumour xenografts induces widespread changes in the microRNA expression profile. Biochem Biophys Res Commun. 2017;494(3-4):700-705.