Subtype‐specific clinical and prognostic relevance of tumor‐expressed F5 and regulatory F5 variants in breast cancer: the CoCaV study

Abstract

Background Tumor expression of certain coagulation factors has been linked to cancer progression. Single nucleotide polymorphisms (SNPs) in F5 (encoding the FV protein) have been found to be associated with breast cancer; however, the role of coagulation factor V (FV) in cancer pathogenesis remains undiscovered. Objectives We aimed to investigate the clinical significance of FV and the regulatory role of F5 gene variants in breast cancer. Patients/Methods A Scandinavian 503-sample breast cancer cohort and three public breast cancer datasets (GOBO, TCGA and KM plotter) were used to determine associations between F5 gene expression (tumor-specific), circulating FV, F5 SNPs, clinical characteristics and breast cancer survival. Immunohistochemistry (IHC) was used to detect FV antigen in tumors. Results F5 expression was 2-fold higher in breast tumors compared with normal tissue, and the presence of FV antigen in breast tumors was confirmed by IHC staining. F5 expression was increased in patients with hormone receptor negative tumors, triple negative tumors, HER2-enriched and basal-like tumors. In patients with basal tumors, high expression of F5 was associated with improved overall survival (hazard ratio, HR = 0.52, 95% confidence interval, 0.31-0.86). SNPs in F5 were associated with tumor size and luminal A tumors. The rs6427202-rs9332542 C-G haplotype, previously associated with breast cancer, displayed a cis-regulatory effect on F5 expression in tumors and plasma FV antigen levels. In silico mining supported this regulatory function. Conclusions FV was a possible marker of aggressive breast cancer, yet also a predictor of favorable outcome. Evaluation of FV expression may be clinically useful for prognosis and treatment decisions in aggressive breast cancer.

Identification of F5 as a Prognostic Biomarker in Patients with Gastric Cancer

“…Thus, it is likely that F5 may contribute to tumourigenesis. Interestingly, our study shows that the high expression of F5 is correlated with a poor OS in GC, and this contradicts a previous study in which high F5 expression improved OS for the basal type of tumours in breast cancer according to the KM-plotter website [7]. However, this could have been caused by failure to exclude other confounding factors and the use of only univariate survival analysis in the study.…”

“…So far, fewer studies have investigated the relationship between F5 and cancer prognosis, including gastric cancer, in which changes in the coagulationfibrinolytic system are often present. The association of the F5 expression level with the survival time of patients with basal breast cancer has been reported by a single study by Tinholt et al [7]. Accumulating evidence suggests that various clotting system factors may influence the prognosis of cancer patients [4,[8][9][10][11][12].…”

“…So far, few studies have explored the prognostic value of the F5 gene expression in F5 has been found to be an oncogene. Tinholt et al analysed a cohort of 1100 breast cancer samples from TCGA and found that the expression of F5 mRNA was about 2-fold higher in breast tumours compared to normal tissues, and its expression increased in patients with late stage tumours [7]. Klee et al also found that the F5 gene was upregulated in cancer tissue compared to nonneoplastic prostate tissue [21].…”

Coagulation factor V is a marker of tumor-infiltrating immune cells in breast cancer

“…5 Moreover, we have shown that genetic variants in the F5 gene are associated with breast cancer susceptibility, 6 and we recently demonstrated that the expression of F5 is increased in breast tumors compared to normal tissue. 7 F5 expression was also linked to breast cancer aggressiveness and overall survival. 7 Because FV is a circulating protein principally synthesized by the liver, its expression in breast tumors suggests a yet undiscovered role for FV in cancer pathogenesis.…”

“…7 F5 expression was also linked to breast cancer aggressiveness and overall survival. 7 Because FV is a circulating protein principally synthesized by the liver, its expression in breast tumors suggests a yet undiscovered role for FV in cancer pathogenesis.…”