Background Prostate cancer patients experience heterogeneous outcomes after radical prostatectomy. Genomic studies including The Cancer Genome Atlas (TCGA) have reported molecular signatures of prostate cancer, but few studies have assessed the prognostic effects of DNA methylation profiles. Methods We conducted the largest methylome subtyping analysis for primary prostate tumors to date, using methylome data from three patient populations: TCGA, a prostate cancer cohort study conducted at the Fred Hutchinson Cancer Research Center (FH), and the Canadian International Cancer Genome Consortium (ICGC) cohort. Four subtypes were detected in the TCGA dataset, then independently assigned to FH and ICGC cohort data. The identified methylation subtypes were assessed for association with cancer prognosis in the above three patient populations. Results Using a set of hypermethylated CpG sites, four methylation subtypes were identified in TCGA. Compared to Subtype 1, Subtype 4 had a hazard ratio (HR) of 2.09 (p=0.029) for biochemical recurrence (BCR) in TCGA patients. HRs of 2.76 (p=0.002) for recurrence and 9.73 (p=0.002) for metastatic-lethal (metastasis or prostate cancer-specific death) outcomes were observed in the FH cohort. A similar pattern of association was noted in the Canadian ICGC cohort, though HRs were not statistically significant. Conclusions A hypermethylated subtype was associated with an increased hazard of recurrence and mortality in three studies with prostate tumor methylome data. Further molecular work is needed to understand the effect of methylation subtypes on cancer prognosis. Impact This study identified a DNA methylation subtype that was associated with worse prostate cancer prognosis after radical prostatectomy.

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