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Tumor expression, plasma levels and genetic polymorphisms of the coagulation inhibitor TFPI are associated with clinicopathological parameters and survival in breast cancer, in contrast to the coagulation initiator TF.

ABSTRACT: Hypercoagulability in malignancy increases the risk of thrombosis, but is also involved in cancer progression. Experimental studies suggest that tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are involved in cancer biology as a tumor- promoter and suppressor, respectively, but the clinical significance is less clear. Here, we aimed to investigate the clinical relevance of TF and TFPI genetic and phenotypic diversity in breast cancer.The relationship between tumor messenger RNA (mRNA) expression and plasma levels of TF and TFPI (? and ?), tagging single nucleotide polymorphisms (tagSNPs) in F3 (TF) (n=6) and TFPI (n=18), and clinicopathological characteristics and molecular tumor subtypes were explored in 152 treatment naive breast cancer patients. The effect of tumor expressed TF and TFPI? and TFPI? on survival was investigated in a merged breast cancer dataset of 1881 patients.Progesterone receptor negative patients had higher mRNA expression of total TFPI (?+?) (P=0.021) and TFPI? (P=0.014) in tumors. TF mRNA expression was decreased in grade 3 tumors (P=0.003). In plasma, total TFPI levels were decreased in patients with larger tumors (P=0.013). SNP haplotypes of TFPI, but not TF, were associated with specific clinicopathological characteristics like tumor size (odds ratio (OR) 3.14, P=0.004), triple negativity (OR 2.4, P=0.004), lymph node spread (OR 3.34, P=0.006), and basal-like (OR 2.3, P=0.011) and luminal B (OR 3.5, P=0.005) molecular tumor subtypes. Increased expression levels of TFPI? and TFPI? in breast tumors were associated with better outcome in all tumor subtypes combined (P=0.007 and P=0.005) and in multiple subgroups, including lymph node positive subjects (P=0.006 and P=0.034).This study indicates that genetic and phenotypic variation of both TFPI? and TFPI?, more than TF, are markers of cancer progression. Together with the previously demonstrated tumor suppressor effects of TFPI, the beneficial effect of tumor expressed TFPI on survival, renders TFPI as a potential anticancer agent, and the clinical significance of TFPI in cancer deserves further investigation.

SUBMITTER: Tinholt M

PROVIDER: S-EPMC4423106 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Tumor expression, plasma levels and genetic polymorphisms of the coagulation inhibitor TFPI are associated with clinicopathological parameters and survival in breast cancer, in contrast to the coagulation initiator TF.

Tinholt Mari M Vollan Hans Kristian Moen HK Sahlberg Kristine Kleivi KK Jernström Sandra S Kaveh Fatemeh F Lingjærde Ole Christian OC Kåresen Rolf R Sauer Torill T Kristensen Vessela V Børresen-Dale Anne-Lise AL Sandset Per Morten PM Iversen Nina N

Breast cancer research : BCR 20150326

<h4>Introduction</h4>Hypercoagulability in malignancy increases the risk of thrombosis, but is also involved in cancer progression. Experimental studies suggest that tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are involved in cancer biology as a tumor- promoter and suppressor, respectively, but the clinical significance is less clear. Here, we aimed to investigate the clinical relevance of TF and TFPI genetic and phenotypic diversity in breast cancer.<h4>Methods</h4>The relatio ...[more]

PMID: 25882602

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Project description:BackgroundDevelopment of inhibitors to transfused factor VIII in patients with hemophilia A continues to be a challenge for professionals involved in hemophilia care. The majority of patients in India receive 'on-demand' rather than prophylactic therapy. The present study was done to assess the prevalence of factor VIII inhibitors in patients with hemophilia A (PWHA) receiving 'on-demand' therapy in a North Indian population and to study the clinicopathological parameters influencing the development of inhibitors.MethodsThe study group comprised of 300 PWHA. Detailed clinical parameters, treatment history, bleeding profile including family history were recorded. Diagnosis of hemophilia A was confirmed by relevant coagulation tests. Inhibitors were screened using mixing based studies followed by quantification by Bethesda assay and Nijmegen modified Bethesda assay. Samples were collected from five cities in North India where a free supply of factor VIII was available and effectively used in three of these cities.ResultsIn the 300 PWHA, disease phenotype was severe in 219 (73%), moderate in 62 (20.67%) and mild in 19 (6.34%), based on the factor VIII bioassay. Inhibitor prevalence was 9.6% (n = 29) and seen only in the severe phenotype. Inhibitor titers ranged from 0.8 to 108.8 BU/ml. A total of 12 PWHA had low and 17 had high titers. Correlation of various clinicopathological parameters in inhibitor-positive versus negative PWHA showed significant correlation with age at onset of disease, severity of disease, age at first exposure to treatment, annual factor intake (IU/kg/year), intense treatment episodes and bleeding manifestations like central nervous system bleed and hematuria. The total study sample had blood group B in 33.34% PWHA, followed by O (27.34%), A (24.34%) and AB (15%), however, in inhibitor-positive samples, significant inhibitor formation was associated with the ABO subtype A (19/29, 65.51%).ConclusionsFactor VIII inhibitor prevalence in PWHA receiving 'on-demand' therapy was 9.6%. Clinicopathological correlates of inhibitor development in such PWHA have been analyzed in this novel study.

Project description:BACKGROUND:Tissue factor pathway inhibitor (TFPI) polymorphisms are known to be involved in venous thrombosis; however, any correlation between the TFPI polymorphisms rs8176592, rs10931292, and rs10153820 and venous thrombosis remains controversial. This meta-analysis aimed to elucidate the relationship between these TFPI polymorphisms and the susceptibility to venous thrombosis. METHODS:A literature search for relevant studies was conducted in PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang Med Online databases. Odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were calculated using fixed-effect/random-effect models by the STATA 12.0 software. Sources of heterogeneity were analyzed by subgroup analysis. RESULTS:Eleven case-control studies involving 3740 subjects (1362 venous thrombosis patients and 2378 healthy controls) were included. The TFPI rs8176592 polymorphism was associated with increased risk of venous thrombosis in the whole population, while no significant association was found between rs10931292/rs10153820 and venous thrombosis. In subgroup analysis based on ethnicity, an increased risk was observed with rs8176592 polymorphism in Asians (Recessive model, OR?=?1.48, 95% CI?=?1.06-2.07, P?=?.023). An increased risk associated with rs10931292 was identified in non-Asians (Recessive model, OR?=?1.42, 95% CI?=?1.03-1.97, P?=?.033). No significant association was found in either Asians or non-Asians with the rs10153820 polymorphism. In subgroup analysis based on source of controls, increased risks were identified in the hospital-based group with rs8176592 polymorphism and in the population-based group with rs10931292 polymorphism, whereas decreased risk was identified in the hospital-based group with the rs10931292 and rs10153820 polymorphisms. CONCLUSION:Meta-analysis suggested that different TFPI polymorphisms may have different associations with venous thrombosis. TFPI rs8176592 polymorphism may increase the risk of venous thrombosis, especially in Asians and hospital-based patients. The TFPI rs10931292 polymorphism may increase the venous thrombosis risk for both non-Asians and population-based patients. Moreover, rs10931292 and rs10153820 polymorphisms of TFPI may decrease the risk of venous thrombosis for hospital-based patients.

Dataset Information

Tumor expression, plasma levels and genetic polymorphisms of the coagulation inhibitor TFPI are associated with clinicopathological parameters and survival in breast cancer, in contrast to the coagulation initiator TF.

Publications

Tumor expression, plasma levels and genetic polymorphisms of the coagulation inhibitor TFPI are associated with clinicopathological parameters and survival in breast cancer, in contrast to the coagulation initiator TF.

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