Abstract
Background: Biochemical recurrence (BCR) after radical prostatectomy indicates poor prognosis in patients with prostate cancer (PCA). DNA methylation (DNAm) is a critical factor in tumorigenesis and has attracted attention as a biomarker for the diagnosis, treatment, and prognosis of PCA. However, the predictive value of DNAm-derived differentially expressed genes (DMGs) in PCA with BCR remains elusive. Methods: We filtered the methylated genes and the differentially expressed genes (DGEs) for more than 1,000 clinical samples from the TCGA cohort using the chAMP and DESeq2 packages of R language, respectively. Next, we integrated the DNAm beta value and gene expression data with the Mithymix package of R language to obtain the DMGs. Then, 1,000 times Cox LASSO regression with 10-fold cross validation was performed to screen signature DMGs and establish a predictive classifier. Univariate and multivariate cox regressive analyses were used to identify the prognostic factors to build a predictive model, and its performance was measured by receiver operating characteristic, calibration curves, and Harrell’s concordance index (C-index). Additionally, a GEO dataset was used to validate the prognostic classifier. Results: One hundred DMGs were mined using the chAMP and Methymix packages of R language. Of these, seven DMGs (CCK, CD38, CYP27A1, EID3, HABP2, LRRC4, and LY6G6D) were identified to build the prognostic classifier (Classifier) through LASSO analysis. Moreover, univariate and multivariate Cox regression analysis determined that the Classifier and pathological T stage (pathological_T) were independent predictors of BCR (hazard ratio (HR 2.2), (95% CI 1.4–3.5), p < 0.0012, and (HR 1.8), (95% CI 1.0–3.2), p < 0.046). A nomogram based on the Classifier was constructed, with high prediction accuracy for BCR-free survival in TCGA and GEO datasets. GSEA enrichment analysis showed that the DMGs were mainly enriched in the metabolism pathways. Conclusion: We identified and validated the nomogram of BCR-free survival for PCA patients, which has the potential to guide treatment decisions for patients at differing risks of BCR. Our study deepens the understanding of DMGs in the pathogenesis of PCA.
Highlights
Prostate cancer (PCA) is a common cancer with the highest prevalence among men worldwide
By comparing the mRNA expression between PCA tissues and nontumorous prostate tissues, we identified 3,023 DEGs for further analysis
After identifying 9,574 methylated genes, we evaluated the level of methylation and gene expression level of 1,285 methylated genes from 397 PCA samples and the methylation level of these 1,285 methylation-associated genes from 49 non-tumor samples by integrating the datasets
Summary
Prostate cancer (PCA) is a common cancer with the highest prevalence among men worldwide. Radical prostatectomy (RP) is considered as an effective therapy for the treatment of localized PCA. Some studies and guidelines have indicated that PSA cannot be used to predict BCR for each patient with PCA, especially when its value is very low (Eisenberg et al, 2010; Fendler et al, 2019; Wang et al, 2020). Among patients with high-risk PCA and clinical stage ≥ T3a, a biopsy Gleason score of 8–10, and/or a serum PSA level >20 ng/ml, approximately 60% had at least 15 years of metastasis-free survival after RP, indicating that not all patients had poor prognosis (Spahn et al, 2010a; Spahn et al, 2010b). Biochemical recurrence (BCR) after radical prostatectomy indicates poor prognosis in patients with prostate cancer (PCA). The predictive value of DNAm-derived differentially expressed genes (DMGs) in PCA with BCR remains elusive
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