The role of polymorphisms in coagulation factor genes in cancer susceptibility

 

Mari Tinholt1,2, Nina Iversen1 and Per Morten Sandset2,3,*,

1Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.  
2Department of Haematology, Oslo University Hospital, Oslo, Norway.

3Institute of Clinical Medicine, University of Oslo, Oslo, Norway.


 

The bidirectional link between cancer and thrombosis observed in epidemiological studies is well recognized. More recently, blood coagulation proteins have been proposed to play a role in cancer progression. Experimental data suggest that coagulation factors like tissue factor (TF), factor (F) VIIa, and FXa have tumor promoting effects [1-3], while the coagulation inhibitor TF pathway inhibitor (TFPI) exerts anti-tumor effects [4-6]. How the coagulation system relates to cancer etiology and risk at the genetic level is, however, largely unexplored.

The FV Leiden (rs6025) and the prothrombin gene G20210A (rs1799963) thrombophilic variants are the most studied polymorphisms in coagulation genes, but there is lack of consensus across studies. Only one cancer study has hitherto been large enough to study homozygous FV Leiden carriers [7], and this study found that homozygous carriers of FV Leiden had a 6-fold increased risk of colorectal cancer. No homozygous carriers of the prothrombin gene G20210A were observed. Heterozygosity for either the FV Leiden or the prothrombin gene G20210A variants was associated with a 30% reduced risk of colorectal cancer. Moreover, while another study reported a higher frequency of heterozygous carriers of the prothrombin gene G20210A variant in gastrointestinal cancer [8], most studies do not support a major role for FV Leiden or prothrombin G20210A heterozygosity as risk factors for solid cancer susceptibility [8-14].  

The role of the more common variants of coagulation genes in cancer susceptibility is yet underreported for most cancer types. Only breast cancer studies have addressed the association between single nucleotide polymorphisms (SNPs) in coagulation pathway genes and cancer risk (Fig. 1).


 

Figure 1. The position of common SNPs in coagulation pathway genes that are associated with risk of breast cancer. The SNP ID numbers of breast cancer associated SNPs in F5, F7, F10, and EPCR [15, 16] are indicated by pins. Exons, introns, and 5' UTRs for each gene are indicated by boxes, lines, and dashed lines, respectively.


One Turkish study investigated selected polymorphisms of the F7 gene and demonstrated that the promoter SNP -402GA (rs510317) was associated with increased susceptibility of breast cancer [15]. In our Norwegian breast cancer study, we investigated 37 tagSNPs located in genes of the tissue factor pathway. We found that six SNPs in either the F5, F10, or EPCR genes were associated with breast cancer (F5 rs12120605, F5 rs6427202, F5 rs9332542, F5 rs6427199, F10 rs3093261, EPCR rs2069948) [16]), suggesting a possible role for these variants in breast cancer etiology. All F5 SNPs were independent of FV Leiden, and tended to be preferentially associated with hormone receptor negative and triple negative patients, thus reflecting the heterogeneity of breast cancer disease. The SNPs in our study could not explain systemic hypercoagulability (higher D-dimer levels, higher peak thrombin and increased activated protein C resistance), but could still contribute to the coagulation regulation within the tumor microenvironment. The F5 SNPs were later confirmed to regulate F5 expression in breast tumors (unpublished).

            The differences in cancer susceptibility in the normal population are likely attributable to common genetic variation, of which SNPs are the most common. Genome-wide and candidate gene association studies revealing putative risk loci have increased our biological insights into carcinogenesis. However, the individual risk contribution of SNPs is typically small and SNPs may be indirectly linked to the true causal variant(s) through linkage disequilibrium rather than being the causal variant itself. The interpretation of the results from genetic association studies have therefore been challenging.

SNPs are found in both coding and non-coding regions and they may have functional effects relevant to disease phenotypes (Fig. 2). 


 

Figure 2. Possible effects of SNPs in coagulation pathway genes. Coding SNPs may affect protein function, translation efficiency, and transcription start or termination signals. Non-coding SNPs may affect mRNA transcription factor binding/splicing/stability, non-coding RNA transcription and function, and epigenetic features. This may potentially lead to a clinically relevant imbalance between pro- and anti-coagulants in cancer patients that may accelerate cancer progression.


It is now believed that true disease associated SNPs exert their effects by altering gene expression. High-throughput sequencing of human genomes, transcriptomes and epigenomes have opened new horizons to understand the genetic basis of oncogenesis and revealing translational research opportunities. Hopefully, this will motivate more groups to perform research aiming to better describe the intricate relationship between cancer and coagulation at the genetic level. One initial approach could be to epigenetic markers and open chromatin regions to identify SNPs in or near coagulation genes that reside in regulatory regions, such as transcription factor binding sites. Disclosing the role of such polymorphisms in genes of the coagulation system on cancer risk and gene expression may be clinically useful and represents one means to achieve a mechanistic understanding of the hemostatic abnormalities in cancer patients. Increased knowledge within the field of cancer and coagulation has the potential to be translated into more individualized approaches for management and prevention of cancer and cancer-associated thrombotic complications.


 

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  • Per Morten Sandset

    Per Morten Sandset

    Director Research, Innovation and Education, Senior Consultant, Professor, MD, PhD - Southeastern Norway Health Authority, Oslo University Hospital and University of Oslo - Research Institute of Internal Medicine and Department of Haematology, Oslo, Norway
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