Expression And Clinical Significance Of ATM In Prostate Cancer

Objective:Prostate cancer is the most common malignancy of male urinary system tumor,which seriously harms the physical health of Chinese men.ATM(Ataxia telangiectasia mutated)is a mutated gene of ataxia telangiectasia,which plays an important role in the evolution of many tumors.For example,ATM is a susceptibility gene for breast cancer,and female ATM mutation carriers have a higher risk of breast cancer.The inactivation of ATM gene promotes the malignant progression of oral squamous cell carcinoma.However,the function of ATM in prostate cancer is still unclear and deserves further study.It has been reported that ATM has a pro-cancer effect in prostate cancer,but other literatures have reported that ATM may be a protective gene and show a tumor suppressor effect.There are positive and negative reports on the relationship between ATM and prostate cancer,but it is certain that the function of ATM is closely related to the biological behavior of prostate cancer cells and the prognosis of patients.To investigate the expression and clinical significance of ATM in prostate cancer by analyzing the expression of ATM and its relationship with clinicopathological features and prognosis.Methods:(1)Based on the prostate cancer samples and normal control samples in the TCGA database,the relevant sample data from TCGA and GTEx in the GEPIA website were integrated,and the different clinicopathological characteristics were included in the groups,and the expression differences of ATM were analyzed.(2)The relationship between ATM expression level and overall survival of patients was analyzed based on TCGA database,and the relationship between ATM expression level and Gleason score and overall survival and biochemical relapse-free survival of patients was analyzed,Kaplan-meier survival curves were generated using the "Survival" package and the "survminer" package.(3)The functions and pathways of ATM were annotated based on GO database and KEGG database.The protein interaction relationship of ATM was analyzed and visualized based on STRING database,and the difference of ATM methylation level was analyzed based on TCGA database.(4)From April 2015 to December 2020,pathological sections of 94 patients with prostate cancer who underwent radical resection of prostate cancer in the Department of Urology of our hospital were collected.Immunohistochemical staining was used to detect and analyze the expression difference of ATM in prostate cancer and adjacent tissues.Relationship between ATM expression and clinicopathological features and biochemical recurrence.(5)Statistical methods: Chi-square test and Fisher test were used for categorical data,Univariate and multivariate COX regression models were used,Kaplan-Meier method was used for survival curves,and Log-Rank test was used for difference analysis between groups,SPSS22.0 was used for statistical software,and Graphad5.0was used for survival curve drawing,P < 0.05 was statistically significant.Results:(1)TCGA and GTEx database analysis showed that the expression level of ATM in prostate cancer samples was lower than that in normal control samples(median3.123 vs 3.554),and the difference was significant(P < 0.001).(2)Based on TCGA database analysis,it was found that the overall survival rate of prostate cancer patients in ATM high expression group was higher than that in ATM low expression group at most time points.(3)GO functional annotation found that ATM was associated with 110 GO terms,including DNA damage-induced protein phosphorylation,DNA damage response,etc.KEGG pathway annotation showed that ATM was involved in p53 signaling pathway and cell cycle.(4)Based on STRING database,a total of 10 proteins were found to have direct interaction with ATM protein,including TP53 protein.GO and KEGG annotation and enrichment analysis of ATM and its interacting proteins showed that these proteins were significantly enriched in biological processes such as DNA repair and signal transduction in response to DNA damage,as well as in cell cycle and homologous recombination pathways.(5)TCGA database analysis showed that ATM methylation level in prostate cancer tissues was significantly higher than that in normal tissues(P < 0.001).(6)Immunohistochemical staining showed that the high expression rate of ATM in adjacent tissues(62.8%)was significantly higher than that in prostate cancer tissues(47.9%),and the difference was statistically significant(P = 0.04).ATM expression was significantly correlated with Gleason score,pathologic stage p T,positive surgical margin and biochemical recurrence(P < 0.05),but not with age,PSA,nerve invasion and lymph node metastasis(P > 0.05).Univariate and multivariate COX regression analysis showed that low expression of ATM was an independent risk factor for biochemical recurrence(P = 0.008,HR = 3.576).Kaplan-Meier analysis showed that patients with high ATM expression had significantly longer biochemical relapse-free survival than those with low ATM expression(P < 0.001).Conclusion:(1).ATM may be a tumor suppressor gene in prostate cancer and may be a new therapeutic target.(2).By analyzing the expression of ATM in prostate cancer,it may have a role in predicting biochemical recurrence,providing effective information for clinical practice and helping to develop personalized treatment plan.