Construction Of A Predictive Model For Prostate Cancer Recurrence-free Survival Based On The E2F Pathway And Research On The Biological Functions Of Key Genes

Background: The biochemical recurrence（BCR）of prostate cancer（PCa）significantly affects the prognosis of prostate cancer patients,and in the current study,we explored the signaling pathway and key genes that related to the biochemical recurrence of prostate cancer,and to reveal its underlying mechanism.Methods: Five cohorts from The Cancer Genome Atlas（TCGA）and Gene Expression Omnibus（GEO）databases were downloaded,and gene set variation analysis（GSVA）was performed between PCa patients with and without biochemical recurrence.We overlapped the results of GSVA and extracted the corresponding gene list,and univariate Cox regression was used to select BCR-related genes,and LASSO-Cox regression analysis was further used to identify BCR-related genes,and the E2F-related gene signature that predicted the biochemical recurrence-free survival（RFS）of PCa was established and validated.Additionally,a nomogram based on the E2F-related gene signature was built and validated.MTT and colony formation assays were conducted to validate the results of bioinformatics analysis.Results: Compared to PCa patients without biochemical recurrence,the E2 F signaling pathway was activated in PCa patients with biochemical recurrence.The gene list of the E2 F signaling pathway was extracted.Based on the identified BCR-related genes,we established an E2F-related gene signature to predict the biochemical recurrence free survival of PCa patients in the Memorial Sloan Kettering Cancer Center（MSKCC）cohort.The E2F-related gene signature was established based on the four identified E2F-related genes,including CDKN2 C,CDKN3,RACGAP1,and RRM2.Based on the expression levels of CDKN2 C,CDKN3,RACGAP1,and RRM2 and their corresponding coefficients,the risk score of each patient in the MSKCC cohort was calculated.PCa patients with low-risk scores exhibited an increased biochemical recurrence free survival than patients with high-risk scores.Receiver operating characteristic（ROC）curve analysis showed the good performance and prognostic accuracy of the E2F-related gene signature,which was validated by the TCGA-prostate adenocarcinoma（TCGA-PRAD）cohort.Subgroup analysis showed that compared to patients with low Gleason scores and early T stages,PCa patients with high Gleason scores and advanced T stages had high-risk scores.In the MSKCC cohort,the E2F-related gene signature-based nomogram was built,which showed good performance in predicting the recurrence free survival of PCa patients,which was validated in the by the TCGA-PRAD cohort.Moreover,in vitro functional experiments found that knockdown of CDKN2 C and RACGAP1 significantly inhibited the proliferation and colony formation of PCa cells,which further confirmed the results of bioinformatics analysis.Conclusions: The E2 F signaling pathway is associated with the biochemical recurrence of PCa,and the identified four E2F-related genes played an important role in the progression of PCa,and the established E2F-related gene signature and nomogram showed good performance in predicting the biochemical recurrence of PCa.