The quest for personalized management of thrombosis in cancer - do cancer genes hold the clue?

Cancer associated thrombosis (CAT) is perplexing.

Spite of over 150 years of recorded history, considerable prevalence and morbidity linked to venous thromboembolism (VTE), which can be fatal, as well as extensive research efforts the causes and mechanisms of cancer related clotting abnormalities remain elusive. Consequently, the prophylactic and therapeutic countermeasures continue to rely on targeting the common coagulation pathway; the effect rather than primary cause of the problem. Not surprisingly, while there has been a great deal of progress, permanent successes have been limited and bleeding risks remain daunting amidst variability of clinical presentations, severity and outcomes across the vast cancer spectrum. Indeed, there is a dire need for more personalized approaches to risk assessment and management of CAT and VTE1.  

A unique approach to this problem has recently emerged from the work published by Henri Versteeg and his colleagues in the February 2018 issue of the Journal of Thrombosis and Haemostasis2. In a small but carefully designed case control study focusing on patients with colorectal cancer (CRC) with and without VTE these investigators turned their analytical gaze away from the traditional preoccupation with the clotting system and asked what specific features of cancer cells themselves make some cancers more prone to trigger VTE than others. With the use of next generation RNA sequencing and precise isolation of cancer cells a using laser capture microdissection technique (LCM) researchers were able to compare gene expression profiles in pairs of CRC patients, one with and one without VTE, but otherwise carefully matched for demographic and clinical characteristics. In this manner it was possible to remove as many confounders as possible and detect features of the underlying cancer that co-segregated with thrombosis.

The striking observation is that different sets of cancer genes were up - or down-regulated in conjunction with VTE depending on whether the clotting event occurred prior to, or at the time of CRC diagnosis (within 3 months). While the specific genes detected in patients with VTE contained few if any coagulant ‘suspects’, the computational analysis of their most prominent expression changes enabled these investigators to re-construct biological processes (pathways) in which these respective VTE-linked genes are known to be involved. This approach revealed that pathways related to inflammation, coagulation, methionine degradation, liver X receptor (LXR), retinoid X receptor (RXR) and interferons track with cancers associated with VTE occurring either before or at CRC diagnosis. The authors also validated the expression of proinflammatory chemokine CLC2 and fibrin deposits in cancer tissues of patients who experienced VTE. These findings suggest that some of the features of cancer cells and the microenvironment they orchestrate may contain the ultimate triggers of VTE and as such hold promise as possible and hitherto unappreciated therapeutic targets and biomarkers of impending thrombosis.

This study represents a unique foray into the possible determinants of CAT that are embedded in the molecular circuitry of the underlying cancer. The sample size is relatively small (9 patient pairs), but the analysis was unbiased, comprehensive and informative. Interestingly, several genes revealed by this analysis have not been studied in the context of CAT before, and their possible causal involvement represents a fascinating and important challenge for future studies. It would also be of great interest to make similar comparisons of cancer genes in other tumour types and subtypes in which VTE is common, but paradoxically difficult to predict according to traditional hematological and clinical criteria3. Notably, some of the genes (e.g. REG4) predictive of thrombosis in CRC patients in the Versteeg cohort could be targets of oncogenic transformation including the impact of mutant KRAS4, which is already known to upregulate the procoagulant phenotype of CRC cells5 and predict VTE risk in CRC patients6. Similar linkages between molecular cancer causation, gene expression and coagulant phenotypes have also been observed in glioblastoma7,8.

Finally, it would be of great interest to explore whether transcripts and proteins described by Versteeg and colleagues could be detected prior to VTE onset using blood tests based on profiling of extracellular vesicles (exosomes) released from cancer cells (5). These and other open questions highlight new and fascinating opportunities to personalize VTE management, a possibility that the work of Versteeg and his colleagues brought to light.


REFERENCES

  1. D'Asti E, Rak J. Biological basis of personalized anticoagulation in cancer: oncogene and oncomir networks as putative regulators of coagulopathy. Thromb Res 2016;140 Suppl 1:S37-43.
  2. Unlu B, van Es N, Arindrarto W, Kielbasa SM, Mei H, Westerga J, et al. Genes associated with venous thromboembolism in colorectal cancer patients. J Thromb Haemost 2018;16(2):293-302.
  3. Khorana AA. Venous thromboembolism and prognosis in cancer. Thromb Res 2010;125(6):490-3.
  4. Garcia-Aguilar J, Chen Z, Warden C, Avila K, Zhou N, Yuan Y-C, et al. Gene expression profiles of rectal cancers with mutant or wild-type Kras. J Clin Oncol 2013;31(4_suppl):414.
  5. Yu JL, May L, Lhotak V, Shahrzad S, Shirasawa S, Weitz JI, et al. Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis. Blood 2005;105(4):1734-41.
  6. Ades S, Kumar S, Alam M, Goodwin A, Weckstein D, Dugan 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.
  7. Magnus N, Gerges N, Jabado N, Rak J. Coagulation-related gene expression profile in glioblastoma is defined by molecular disease subtype. J Thromb Haemost 2013;11(6):1197-200.
  8. Riedl J, Preusser M, Nazari PM, Posch F, Panzer S, Marosi C, et al. Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism. Blood 2017;129(13):1831-9.
  • Janusz Rak

    Janusz Rak

    Jack Cole Chair in Pediatric Hematology/Oncology Professor, Department of Pediatrics McGill University, The Research Institute of the McGill University Health Centre Montreal Children's Hospital
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