Comprehensive methylome sequencing reveals prognostic epigenetic biomarkers for prostate cancer mortality

作者：Ruth Pidsley, Dilys Lam, Wenjia Qu, Timothy J. Peters, Phuc‐Loi Luu, Darren Korbie, Clare Stirzaker, Roger J. Daly, Phillip D. Stricker, James G. Kench, Lisa G. Horvath, Susan J. Clark · 发表于：Clinical and Translational Medicine · 年份：2022 · DOI：10.1002/ctm2.1030 · 被引用次数：24 · 研究领域：Epigenetics and DNA Methylation、Prostate Cancer Diagnosis and Treatment、Ferroptosis and cancer prognosis

BACKGROUND: Prostate cancer is a clinically heterogeneous disease with a subset of patients rapidly progressing to lethal-metastatic prostate cancer. Current clinicopathological measures are imperfect predictors of disease progression. Epigenetic changes are amongst the earliest molecular changes in tumourigenesis. To find new prognostic biomarkers to enable earlier intervention and improved outcomes, we performed methylome sequencing of DNA from patients with localised prostate cancer and long-term clinical follow-up. METHODS: We used whole-genome bisulphite sequencing (WGBS) to comprehensively map and compare DNA methylation of radical prostatectomy tissue between patients with lethal disease (n = 7) and non-lethal (n = 8) disease (median follow-up 19.5 years). Validation of differentially methylated regions (DMRs) was performed in an independent cohort (n = 185, median follow-up 15 years) using targeted multiplex bisulphite sequencing of candidate regions. Survival was assessed via univariable and multivariable analyses including clinicopathological measures (log-rank and Cox regression models). RESULTS: WGBS data analysis identified cancer-specific methylation patterns including CpG island hypermethylation, and hypomethylation of repetitive elements, with increasing disease risk. We identified 1420 DMRs associated with prostate cancer-specific mortality (PCSM), which showed enrichment for gene sets downregulated in prostate cancer and de novo methylated in cancer. Through...