Cancer-associated thrombosis (CAT) is one of the leading causes of non-cancer-related deaths in patients with cancer receiving systemic therapy. The association between cancer and thromboembolic disease is well known, but the mechanisms that promote thromboembolic events in cancer are multifaced and not fully understood .
Several risk factors increase a cancer patient’s risk of developing thrombosis, such as age, ethnicity and immobility, along with cancer type, stage and site, and chemotherapy.
It is estimated that approximately 4–20% of cancer patients will experience venous thromboembolism (VTE) at some stage. Annually, 0.5% of cancer patients will experience thrombosis compared with a 0.1% incidence rate in the general population .
CAT management is an evolving field, with the constant development of direct oral anticoagulants and best practice improvement. To effectively manage CAT, it is paramount to know the risk of each patient. Several risk assessment models exist to guide clinical decisions and predict primary and recurrent VTE, such as Khorana, ONKOTEV, PRO-TECHT, and many more [3–5]. However, these models have mixed performances and require further refinement to improve discrimination and identify high-risk patients.
To improve these prediction models, measurable biomarkers, which are measurable biologic parameters, can separate patients with different risks. In this respect, extracellular miRNAs are promising biomarkers for CAT.
miRNA as biomarkers for CAT
miRNAs are non-coding RNA molecules of about 20–22 nucleotides that inhibit gene expression at the post-transcriptional level by pairing up with the target messenger RNA and inducing translation inhibition or RNA degradation. A single miRNA can regulate different genes, and each gene can be regulated by different miRNA. They can be found intracellularly and extracellularly in body fluids (such as plasma and serum), where they are transported by carriers, such as macrovesicles, exosomes, and lipoproteins. When they bind to their carriers, miRNAs are very stable because they are protected from RNase activity. For their stability, they have emerged as a promising class of biomarkers for many diseases . Despite their promising role, studies on the use of miRNAs as biomarkers for CAT are still limited.
A case–control study of colorectal cancer patients identified nine miRNAs that were significantly downregulated in the blood of colorectal cancer patients who developed VTE compared with controls. Colorectal cancer patients may express unique miRNA profiles right before VTE development, which may be used as biomarker in future predictive models. The study also identified potential new mechanistic targets for understanding CAT, suggesting that inhibitory miRNAs’ downregulation may cause disinhibition of pathways important for platelet and vascular function and other prothrombotic factors .
A study by Oto and colleagues identified a profile of miRNA at diagnosis able to predict a VTE event in pancreatic ductal adenocarcinoma (PDAC) and distal extrahepatic cholangiocarcinoma (DECC) patients during follow-up. The study divided patients into screening (n=10) and confirmatory groups (n=32) and identified seven miRNAs (miR-486-5p, miR-106b-5p, let-7i-5p, let-7g-5p, miR-144-3p, miR-19a-3p and miR-103a-3p) to be included in a predictive model. Applying the predictive model, it was possible to estimate each PDAC and DECC patient’s thrombotic risk at study inclusion and the median thrombotic risks of the group of patients who suffered a VTE during follow-up and who did not, which were 0.72 and 0.13, respectively.
In addition, to further understand the biological mechanism potentially dysregulated by these miRNAs, researchers identified their targets and pathways. Most of the identified miRNAs had targets involved in the pancreatic cancer pathway and the complement and coagulation cascades. They also identified seven miRNAs (miR-30e-3p, let-7i-5p, let-7g-5p, miR-144-3p, miR-199a-3p, miR-101-3p and miR-15a-5p) that are significantly downregulated in PDAC and DECC patients right before the VTE event compared with inclusion at diagnosis. Interestingly, four of these seven miRNAs are upregulated in VTE patients at inclusion than non-VTE patients and downregulated right before the VTE event compared with inclusion, meaning that these miRNAs are strong candidates for prompting a thrombotic complication in PDAC and DECC patients .
However, the number of events included in this study is small for the number of predictors included in regression modeling. Patients from the screening cohort were also included in the confirmatory group, leading to a highly overfit model and results. Nevertheless, miRNAs are a growing field of study in CAT, and further studies are needed.
Despite promising candidate biomarkers, miRNA may be challenging for research and clinical use. They have multiple transport mechanisms, are difficult to isolate and analyze, and lack widespread standards. In particular, the lack of endogenous normalization controls hinders miRNA analysis. Furthermore, significant biases in RNA isolation and library preparation kits can impact the results.
Keep reading the ASH series:
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- Sud R, Khorana AA. Cancer-associated thrombosis: risk factors, candidate biomarkers, and a risk model. Thromb Res. 2009;123 Suppl 4:S18-S21. doi:10.1016/S0049-3848(09)70137-9
- Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-4907. doi:10.1182/blood-2007-10-116327
- Verso M, Agnelli G, Barni S, Gasparini G, LaBianca R. A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: the Protecht score. Intern Emerg Med. 2012;7(3):291-292. doi:10.1007/s11739-012-0784-y
- Cella CA, Di Minno G, Carlomagno C, et al. Preventing Venous Thromboembolism in Ambulatory Cancer Patients: The ONKOTEV Study. Oncologist. 2017;22(5):601-608. doi:10.1634/theoncologist.2016-0246
- Morelli VM, Brækkan SK, Hansen JB. Role of microRNAs in Venous Thromboembolism. Int J Mol Sci. 2020;21(7):2602. doi:10.3390/ijms21072602
- Ann S. Kim, Matthew F Kalady, Jennifer DeVecchio, et al. Identifying miRNA biomarkers and predicted targets associated with venous thromboembolism in colorectal cancer patients. Blood 2019;134(Suppl 1):3643. doi: 1182/blood-2019-127585
- Oto J, Navarro S, Larsen AC, et al. MicroRNAs and neutrophil activation markers predict venous thrombosis in pancreatic ductal adenocarcinoma and distal extrahepatic cholangiocarcinoma. Int J Mol Sci. 2020;21(3):840. doi:10.3390/ijms21030840
- Kim AS, Khorana AA, McCrae KR. Mechanisms and biomarkers of cancer-associated thrombosis. Transl Res. 2020;225:33-53. doi:10.1016/j.trsl.2020.06.012