Genetic Basis of Thrombosis in Cancer Esterina D’ Asti, MSc 1,à Nathalie Magnus, MSc 1,à Brian Meehan, BSc 1 Delphine Garnier, PhD 1 Janusz Rak, MD, PhD 1 1 Montreal Children’s Hospital, RI MUHC, McGill University, Montreal, Quebec, Canada à Esterina D’Asti and Nathalie Magnus contributed equally. Semin Thromb Hemost Address for correspondence Janusz Rak, MD, PhD, Montreal Children’s Hospital, Place Toulon, 4060 Suite Catherine West, PT-232, Montreal, Quebec H3Z 2Z3, Canada (e-mail: janusz.rak@mcgill.ca). The vascular system represents the ultimate interface between local tissue cells (normal or malignant) and their systemic and external environments. The integrity of this important boundary is guarded by the hemostatic system, the activation of which is the first step in the biological program governing tissue responses to injury. As such, engagement of the coagulation system is followed by a succession of mecha- nistically interlinked processes of inflammation, angiogene- sis, recruitment of stromal cells, and tissue repair (wound healing) which restore or substitute the structural and func- tional continuity 1–4 (►Fig. 1). The underlying molecular interconnectedness is illustrated by the spectra of biological activities associated with several key mediators (thrombin), regulators (thrombomodulin), products Keywords ► cancer ► tissue factor ► oncogenes ► coagulation ► microparticles Abstract Genetically altered cancer cells both provoke and respond to changes in their microenvironment, stroma, and vasculature. This includes local and systemic activation of the coagulation system, which is a part of the functional continuum involving inflammation, angiogenesis, and tissue repair programs, often reactivated in cancer. These responses coevolve with, and contribute to, the malignant process. Cancer coagulopathy is not only a source of comorbidity and mortality in cancer patients, but it also affects the disease biology including processes of tumor growth, initiation, dormancy, invasion, angiogenesis, metastasis, and therapeutic responsiveness. Notably, genetic and cellular differences between different cancer types are paralleled by a degree of diversity in the related coagulation system perturbations. Although some of these differences may be unspecific, iatrogenic, or indirect in nature, others are affected by oncogenic pathways (RAS, EGFR, HER2, MET, PTEN, and TP53) activated in cancer cells due to driver mutations of critical genes. Such mutations cooperate with hypoxia, cellular differentiation, and other influences to alter the expression of tissue factor, protease-activated receptors (e.g., PAR-1 and PAR-2), coagulation factors (FII and FVII), and other molecules related to the hemostatic system. Oncogenic pathways also control secretion of some of these entities from cancer cells, either as soluble proteins, or as cargo of extracellular vesicles/microparticles. Moreover, emerging evidence suggests that the expression profiles of coagulation-related genes differ between molecularly and genetically distinct subgroups of specific malignancies such as glioblastoma multiforme and medulloblastoma. Certain hereditary thrombophilias may also affect cancer pathogenesis. We suggest that mechanisms of cancer coagulopathy may be more diverse and genetically modulated than hitherto realized. If so, a possibility may exist to deliver more personalized, biologically based, anti- coagulation, and thereby improve patient survival. Issue Theme Cancer and Thrombosis: An Update; Guest Editor, Hau C. Kwaan, MD, FRCP. Copyright © by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI http://dx.doi.org/ 10.1055/s-0034-1370766. ISSN 0094-6176. Downloaded by: McGill University. Copyrighted material.