Development and validation of a novel DNA damage repair-related long non-coding RNA signature in predicting prognosis, immunity, and drug sensitivity in uterine corpus endometrial carcinoma

Abstract

BackgroundDNA damage response (DDR) confer resistance to chemoradiotherapy in cancer cells. However, the role of DDR-related lncRNAs (DRLs) in uterine corpus endometrial carcinoma (UCEC) is poorly understood. In this study, we aimed to identify a DRL-related prognostic signature that could guide the clinical treatment of UCEC. MethodsWe extracted transcriptome and clinical data of patients with UCEC from The Cancer Genome Atlas (TCGA) database and identified DRLs using Spearman correlation analysis. Univariate and multivariate Cox analyses were used to determine candidate prognostic DRLs. The samples were randomly divided into training and test cohorts in a 1:1 ratio. A DRL-related risk signature was constructed from the training cohort data using the least absolute shrinkage and selection operator (LASSO) algorithm, and validated using the test and entire cohorts. Subsequently, a prognostic nomogram was developed using a multivariate Cox regression analysis. The functional annotation, immune microenvironment, tumor mutation burden (TMB), immune checkpoint blockade (ICB) efficacy, and drug sensitivity were also comprehensively analyzed between different risk groups. Finally, the function of AC019069.1 was validated in vitro. ResultsA novel risk signature was developed based on nine DRLs. The risk score efficiently predicted the prognosis of patients with UCEC. Based on the median risk score, two subgroups were identified. The DDR-related pathways were upregulated in the high-risk group. Additionally, high-risk patients have low immune activity, poor response to ICB, and weak sensitivity to chemotherapeutic agents, possibly because of the proficient DDR system. Finally, we demonstrated AC019069.1 could promote cell proliferation, decrease apoptosis and maintain genome stability of UCEC cells. ConclusionsThe developed DRL-related signature can predict the prognosis, immune microenvironment, immunotherapy, and chemoradiotherapy responsiveness of UCEC. Our study also revealed the potential value of DDR-targeted therapy in treating high-risk patients with UCEC.