TBK1 Genetic Variants Associated With Colorectal Cancer Prognosis

Objective:TANK-binding kinase 1(TBK1)is a serine-threonine kinase and a member of the non-canonical IκB(IKK)family.In recent years,many studies have shown that TBK1 can promote cancer development in many tumors.In breast cancer,TBK1up-regulates the expression level of epidermal growth factor receptor(EGFR)in cells,promotes epithelial-mesenchymal transition(EMT)and angiogenesis,leading to breast cancer cells differentiation,invasion and malignancy.In thymoma and melanoma,TBK1 enhances tumor T cell infiltration by inducing dendritic cell function,which reduce tumor growth and promote death.In addition,many studies have shown that TBK1 is closely related to the occurrence and development of pancreatic cancer and breast cancer.In this study,we aim to investigate the association between TBK1 gene variants and the prognosis of colorectal cancer patients in the Chinese population.Methods : 1.The TCGA and GEO databases and the gene expression profiles of GSE21510 and GSE32323 from GEO were used to explore the expression differences of TBK1 in colorectal cancer tumor tissues compared to normal tissues.We analyzed the association between the TBK1 and the prognosis of colorectal cancer in TCGA database.2.We use Haplo View software,functional annotation tools Haplo Reg,SNPinfo to gradually screen out the potential functional SNPs of the TBK1 gene in the whole genome.3.In this cohort,344 patients who were initially diagnosed as colorectal cancer in the Affiliated Nanjing First Hospital and the First Affiliated Hospital of Nanjing Medical University were recruited as the research objects.5 ml of the venous blood was collected from each patient and DNA genotyping.Cox proportional hazard regression was used to calculate the association between TBK1 SNPs and the survival of patients with colorectal cancer,and to adjust potential confounding variables.In addition,we analyzed the association between TBK1 rs61250306 and the overall survival of colorectal cancer stratified by colorectal cancer related pathological factors.Results: We found that patients with the TBK1 rs61250306 G allele have a longer overall survival time than those with the C allele(HR=0.74,95%CI=0.55-1.00,P=0.047).In addition,compared with the CC genotype,individuals with the CG/GG genotype had a lower risk of death from colorectal cancer.It is more common in patients with colorectal cancer by ≤60 years,male,smoking,and well and moderately differentiated tumors.Conclusion: Our research shows that TBK1 rs61250306 is a promising prognostic marker for colorectal cancer,which promotes the personalized treatment of colorectal cancer.