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Semin Thromb Hemost 2019; 45(04): 373-384
DOI: 10.1055/s-0039-1687891
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

Nadim Tawil
1   Montreal Children's Hospital, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada
,
Rayhaan Bassawon
1   Montreal Children's Hospital, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada
,
Janusz Rak
1   Montreal Children's Hospital, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada
› Author Affiliations
Funding This work was supported by the operating grants from the Canadian Institutes for Health Research (CIHR Foundation grants MOP 102736, MOP 111119) and the Canadian Cancer Society Innovation to Impact to J. R., who is also a recipient of the Jack Cole Chair in Pediatric Hematology/Oncology. N. T. was supported by the McGill Integrated Cancer Research Training Program. Infrastructure funds were provided by the Fonds de Recherche en Santé du Quebec.
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Publication Date:
16 May 2019 (online)

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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.

Keywords

coagulome - oncogenes - glioblastoma - molecular classification - single-cell sequencing