Promoter methylation of the immune checkpoint receptor PD-1 (PDCD1) is an independent prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients following radical prostatectomy

Abstract

Biomarkers that facilitate the prediction of disease recurrence in prostate cancer (PCa) may enable physicians to personalize treatment for individual patients. In the current study, PD-1 (PDCD1) promoter methylation was assessed in a cohort of 498 PCa patients included in The Cancer Genome Atlas (TCGA) and a second cohort of 300 PCa cases treated at the University Hospital of Bonn. In the TCGA cohort, the PD-1 promoter was significantly hypermethylated in carcinomas versus normal prostatic epithelium (55.5% vs. 38.2%, p < 0.001) and PD-1 methylation (mPD-1) inversely correlated with PD-1 mRNA expression in PCa (Spearman's ρ = −0.415, p < 0.001). In both cohorts, mPD-1 significantly correlated with preoperative prostate specific antigen (PSA). In univariate Cox Proportional Hazard analysis, mPD-1 served as a significant prognostic factor for biochemical recurrence (BCR)-free survival (Hazard ratio: HR = 2.35 [1.35–4.10], p = 0.003, n = 410) in the TCGA cohort. In multivariate analysis, mPD-1 was shown to add significant independent prognostic information adjunct to pathologic tumor category (pT) and Gleason grading group (HR = 2.08 [1.16–3.74], p = 0.014, n = 350). PD-1 promoter methylation analyses could thus potentially aid the identification of patients which might benefit from adjuvant treatment after radical prostatectomy. Moreover, our data suggest an intrinsic role of PD-1 in PCa carcinogenesis and disease progression, which needs to be addressed in future studies.