Pan-Cancer Analysis and Validation Reveals that D-Dimer-Related Genes are Prognostic and Downregulate CD8+ T Cells via TGF-Beta Signaling in Gastric Cancer

Abstract

Background: Cancer is considered one of the most lethal diseases worldwide. Venous thromboembolism (VTE) is the second leading cause of death in cancer patients. As one of the most reproducible predictors of thromboembolism, the D-dimer level is commonly considered by oncologists. Previous studies have demonstrated that the most correlated genes at the D-dimer level are F3, F5 and FGA.Methods: Using data from TCGA and multiple webtools, including GEPIA2, UALCAN, TIMER2.0, Kaplan-Meier Plotter and CIBERSORTx, we analyzed the tumor mutation burden (TMB), microsatellite instability (MSI) and functions of D-dimer-related genes in cancer. Validation was conducted via quantitative real-time polymerase chain reaction (qRT-PCR) and independent GEO + GTEx cohort. All statistical analyses were performed in R software and GraphPad Prism 9.Results: F3, F5 and FGA were expressed differently in multiple cancer types. TMB, MSI and anti-PD1/PDL1 therapy responses were correlated with D-dimer-related gene expression. D-Dimer-related genes expression affect the survival of cancer patients. F3 and F5 functioned in TGF-beta signaling. F3 and F5 were related to immunity and affected the fraction of CD8+ T cells by upregulating the TGF-beta signaling pathway, forming an F3, F5/TGF-beta signaling/CD8+ T cell axis.Conclusion: F3, F5 and FGA serve as satisfactory GC multibiomarkers and potentially influence the immune microenvironment and survival of cancer patients by influencing TGF-beta signaling.

Genetic variants in African‑American and Hispanic patients with breast cancer

“…SETD8 variants can affect epigenetic pathways due to their role as lysine methyltransferases. SETD8 is also involved in DNA damage repair, thus making it a potential target via small-molecule inhibition (38). Additionally, PRSS1 is associated with drug resistance in cancer and higher cancer risk along with SETD8 and ARID1B (39)(40)(41).…”

“…In colon and breast cancers, 5-Fluorouracila sensitivity is associated with variants in the MTHFR gene ( 36 , 37 ). F5 (Coagulation factor V) is an estrogen response gene associated with CD8+ T cell in cancer immunity ( 30 , 38 ). These genes are also associated with the TGF-β pathway.…”

The Multi-Dimensional Biomarker Landscape in Cancer Immunotherapy

“…Weighted Gene Co-Expression Network Analysis (WGCNA) can be further applied to pinpoint novel transcription factors that are greatly associated with the infiltrated tumor-associated immune cells [ 115 ]. From there, gene expression networks composed of the identified transcription factors and immune-related genes can be constructed and validated by TCGA cancer data to correlate gene expression data to tumorigenesis and patient survival [ 116 , 117 ]. The application of such bioanalytical tools has certainly shed light on the influence of TME components in response to immunotherapy.…”

Preoperative D-dimer and 5-year overall survival rate in patients diagnosed with gastric cancer and undergoing gastric cancer radical surgery: a Retrospective cohort study

“…Therefore, previous studies have shown that elevated D-dimer levels predict poor prognosis in most types of tumors, especially in gastric cancer (19) (20) (21). Due to the visibility and convenience of D-dimers, Dr.Guan Y's team has stated that as one of the most reproducible predictors of thromboembolism, D-dimers should be monitored in cancer patients such as gastric cancer (22). In recent years, research by teams such as Go, S, Liu, L, Suzuki, T, Dai, H, Kim EYetc.…”