TOP2A and PPARGC1A differentiate chromatin regulator-related subtypes for prostate cancer patients undergoing radical prostatectomy

Abstract

Abstract BACKGROUND To find molecular subtypes and risk score that can be used to accurately predict the biochemical recurrence (BCR) after radical prostatectomy (RAP) in prostate cancer (PCa) patients from the perspective of chromatin regulator (CR). METHODS We obtain the differentially expressed genes (DEGs) between tumor and normal samples from the TCGA and GEO databases, and intersected it with CR-related and prognostic genes in the TCGA database. Subsequently, consensus clustering, risk score, functional analysis, tumor immune microenvironment, m6A analysis, and tumor heterogeneity were analyzed through R software 3.6.3 and its suitable packages. RESULTS After taking the intersection, TOP2A and PPARGC1A were identified to construct molecular subtypes and risk score in the TCGA database, which was verified externally using another GEO dataset. Cluster 2 had shorter BCR-free survival than cluster 1 in TCGA (HR: 2.21, 95%CI: 1.32–3.73, p = 0.003), GEO (HR: 2.05, 95%CI: 1.05–4.02, p = 0.01) and MSKCC2010 (HR: 5.93, 95% CI: 1.96–17.87, p < 0.001) databases. Similar results were observed in the high- and low-risk group divided by our risk score on the basis of median value. We have witnessed more significant tumor heterogeneity and higher expression of various m6A genes in the cluster 2. Gene set variation analysis indicated that cell cycle-related pathways were mainly downregulated in the cluster 2. In addition, despite no overall differences in tumor immune microenvironment scores, various tumor-infiltrating immune cells were suppressed in the cluster 2. CONCLUSIONS In our study, TOP2A and PPARGC1A could differentiate prostate cancer subtypes for patients undergoing RAP and help make early plans for subsequent treatment.