Oncogenes and Clotting Factors: The Emerging Role of Tumor Cell Genome and Epigenome in Cancer-Associated Thrombosis

Abstract

There are emerging linkages between biological and genetic aspects of cancer progression and the mechanisms of cancer-associated thrombosis. It is argued that reciprocal influences between cancer cells, their associated vascular stroma, and the hemostatic system may shape the mechanism of coagulopathy. In this regard, glioblastoma multiforme offers a paradigm where the prevalent occurrence of local microthrombosis and peripheral venous thromboembolism can be linked to the profiles of oncogenic driver mutations and their impact on the expression of coagulation-related genes (coagulome). These relationships can be recapitulated in cellular models of glioblastoma, where the expression of tissue factor, podoplanin, and the release of procoagulant microparticles (extracellular vesicles) remains under the control of oncogenic pathways (epidermal growth factor receptor variant III, isocitrate dehydrogenase 1). These pathways define molecular subtypes of glioblastoma that express differential coagulomes. Moreover, single-cell sequencing of glioblastoma samples reveals a combinatorial rather than common profile of both subtype markers and coagulation-related genes. Based on these emerging observations, the authors suggest that cancers may operate as coagulant composites, where individual cells and their dominant populations express different procoagulant phenotypes, resulting in the net impact on the hemostatic system. They suggest that relating these mechanisms to clinical presentations of thrombosis may facilitate a more causality-based, personalized, and possibly cancer-specific thromboprophylaxis and treatment.

Glioblastoma cell populations with distinct oncogenic programs release podoplanin as procoagulant extracellular vesicles

“…3,4 Cancer-associated thrombosis (CAT) is morbid and may also promote disease aggressiveness, 4,5 calling for more effective biologically based countermeasures. 6 Multiple mechanisms have been proposed to contribute to thrombosis in GBM, including vascular abnormalities, overexpression of tissue factor (TF), and release of procoagulant microparticles (extracellular vesicles [EVs]) 7,8 by tumor cells. EVs have attracted special attention because of their presence in the circulation, involvement in CAT in other cancers, 9 and the association between vesiculation processes and genetic GBM progression.…”

“…18 For example, molecular subtypes of GBM (proneural, mesenchymal, and classical), driven by distinct genetic and epigenetic alterations, 19 express different profiles of coagulation-related genes (coagulomes). 6,20 Moreover, several of the underlying driver mutations, including oncogenic forms of epidermal growth factor receptor (EGFRvIII), isocitrate dehydrogenase 1 (IDH1 R132H), loss of phosphatase and tensin homolog (PTEN), and reprogramming of the cellular epigenome, have been implicated in dysregulation of TF, PDPN, and other hemostatic proteins, 6 along with changes in the global prothrombotic phenotype of GBM cells 21 and tumors. 8 The emerging subtype-based GBM stratification 22,23 has recently been challenged by profiling of tumors at the levels of the single-cell transcriptome and epigenome.…”

Leukobiopsy – A Possible New Liquid Biopsy Platform for Detecting Oncogenic Mutations

“…Interestingly, platelets ingest glioblastoma EVs containing oncogenic transcript for EGFRvIII and carry this signature into the circulation (Nilsson et al, 2011). However, certain subtypes of glioblastoma are spared form CAT, due to protective effects associated with the expression of specific transforming mutations, such as those of isocitrate dehydrogenase (IDH1), a phenotype that correlates with reduced expression of tissue factor, podoplanin and other genes (Unruh et al, 2016;Tawil et al, 2019) and with normal platelet counts (Unruh et al, 2016). It is presently unknown, but remains of great interest whether these events affect the levels of blood-borne cancer biomarkers associated with platelets, EVs, or cell-free nucleic acids.…”

Genomic Profiling Identifies Somatic Mutations Predicting Thromboembolic Risk in Patients with Solid Tumors

“…Notably, mutations in KRAS (HR=1. 34 Given the observed effect of STK11 mutations on the risk of CAT, a dedicated analysis was conducted on data from The Cancer Genome Atlas (TCGA) to evaluate the effect of STK11 mutations on RNA expression for tissue factor (F3) and G-CSF (CSF3). Tissue factor is widely believed to be an important effector of CAT and has been shown to be upregulated by several oncogenes.…”