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Abstract
Introduction Genomic instability is a hallmark of cancers, which leads to tumor heterogeneity and tolerance to chemoradiotherapy thus affecting the prognosis. Exploring the DDR gene in the prediction of prognosis, response of ICB and anti-tumor therapy is of great importance.
Methods RNA-seq data was from 19 endometrial cancer patients. 585 patients‘ data were from TCGA. Cox, Kaplan Meier, and Lasso logistic regression were used to screen the univariate factor and build the DDR nomogram. R ‘limma’ package was used to analyze the DEGs between the high and low-risk groups. Enrichment analysis was achieved. Immune infiltration status and ICB response prediction were performed. r-H2AX foci after UBE2T knockdown were analyzed. Comet assay was used to observe the DNA damage caused by UBE2T knockdown. Western blot was used to investigate DDR protein expression.
Results A DDR-related nomogram containing UBE2T and EME1 was established. UBE2T expression increased in high-risk group. The high-risk group showed different infiltration patterns. DDR nomogram exhibits an AUC of 0.764 to predict 3-year prognosis. UBE2T showed an AUC of 0.977 to predict 3-year prognosis. UBE2T mono-ubiquiting FANCD2 is a critical process in ICL repair. Comet assay showed UBE2T knockdown-induced DNA damage, which is enhanced after MMC treatment. FANCD2 ubiquitin decreased after UBE2T knockdown. p-Chk1 and p-ATM increased when exposed to MMC. UBE2T expression level is related to immune receptors such as TNFRSF14, etc.
Conclusion/Implications A DDR genes nomogram with UBE2T as a key variable was identified. This study may help risk stratification and promote DDR agent and ICB use in endometrial cancer.
