Identification And Function Analysis Of A Five-long Noncoding RNA Prognostic Signature For Endometrial Cancer Patients

ObjectiveEndometrial cancer is one of the three most common genital malignancies in women and the second leading cause of death in gynecological tumors.Despite recent advances in the diagnosis and treatment of endometrial cancer and a decrease in mortality,effective prognostic markers are still lacking.This study aimed to construct a long noncoding RNA(lnc RNA)-based prognostic signature to improve the survival prediction for endometrial cancer(EC)patients and guide individualized treatments.Meanwhile,the correlation between TCM syndrome types and prognosis of endometrial cancer patients was analyzed to summarize their special high-risk constitution types,so as to provide reference for the clinical individualized diagnosis and treatment of endometrial cancer.Methods1.m RNA and mi RNA sequencing and clinical data of 526 patients with EC(randomized to training or validation set,n = 263)were collected from The Cancer Genome Atlas database.Differentially expressed genes(DEGs),differentially expressed Lnc RNAs(DELs),and differentially expressed mi RNAs(DEMs)were identified between 263 EC samples and 33 normal controls.2.Lnc RNAs associated with the prognosis of endometrial cancer were obtained by univariate and multivariate COX regression analysis.Furthermore,Lnc RNAs with the most prognostic relevance were obtained,and a linear risk model based on the expression profile of Lnc RNAs was constructed to predict the prognosis of patients.3.Retrospective analysis was performed on 73 cases of endometrial carcinoma treated in the university town of Guangdong Hospital of Traditional Chinese Medicine from January 2012 to December 2014.Clinical data were collected for survival analysis.Risk factors were screened by Kaplan-Meier method,and risk factors were analyzed by Cox proportional hazard model.Results1.Univariate and multivariate Cox regression analyses identified five DELs(LINC00475,LINC01352,MIR503 HG,KCNMB2-AS1,and LINC01143)that were overall survival related.The Kaplan–Meier curve showed that the risk score model established by these five DELs can significantly distinguish the survival ratio of patients at high risk from those at low risk.2.The receiver operating characteristic curve indicated that this risk score exhibited good survival prediction performance,with the area under the curve of 0.978.In addition,this risk score was independent of other clinical factors.Stratification analysis based on two independent prognostic clinical factors(histologic grade and recurrence status)demonstrated that the high-risk score was still a poor prognostic factor for patients with histologic grade 3,recurrence or non-recurrence status.In nomogram model,the risk score was one of the main contributions to survival rates,and its Harrell ’ s concordance index was higher than the other two independent clinical factors,although all lower than the combined.3.Mechanism analyses showed that these Lnc RNAs functioned by coexpressing with DEGs(i.e.,LINC00475-PTGDR,LINC01352/MIR503HG-BACH2,KCNMB2-AS1-PCSK9,LINC01143-NUF2/PTTG1)or as a competing endogenous RNA of DEMs to regulate DEGs(LINC00475-mi R-4728-PTGDR,MIR503HG-mi R-3170-BACH2).4.K-M survival analysis showed that the survival rate of endometrial cancer was related to the surgical-pathological stage,pathological grade,depth of tumor muscle invasion and TCM syndrome type(P<0.05).Late surgical staging,pathological grade G3,muscle infiltration depth >1/2,TCM syndrome differentiation for damp-heat and blood-stasis toxic type has a worse prognosis.Multivariate regression analysis showed that surgical pathological stage and TCM syndrome type were independent factors influencing the prognosis of endometrial cancer(P<0.05).ConclusionSurgical pathological stage,pathological grade,infiltration depth of tumor muscle layer and TCM syndrome type were the influencing factors for the prognosis of endometrial cancer.Multivariate analysis showed that surgical pathological stage and TCM syndrome type were independent factors for the prognosis of endometrial cancer.Our novel risk score system may be a promising prognostic biomarker to guide personalized treatment for endometrial cancer patients and it can add prognostic value for current clinical system.