| dc.description.abstract | Most screening-detected prostate cancer (PCa) is indolent and not lethal. Biomarkers that can predict aggressive diseases independent of clinical features are needed to improve risk stratification of localized PCa patients and reduce overtreatment. Epigenetic, especially methylation biomarkers have better stability in biofluids or samples with a below-average quality. We aimed to identify DNA methylation differences in leukocytes between clinically defined aggressive and non-aggressive PCa to identify potential biomarkers for PCa diagnosis. To accomplish this aim, we performed DNA methylation profiling in leukocyte DNA samples obtained from 287 PCa patients with Gleason Score (GS) 6 and ≥8 using Illumina 450k methylation arrays, and 8 PCa patients using whole genome bisulfite sequencing. We observed the DNA methylation level in the core promoters and the first exon region were significantly higher in GS≥8 patients than GS=6 PCa. We then performed a 5-fold cross validated random forest model on 1,459 differentially methylated CpG Probes (DMPs) between the GS=6 and GS≥8 groups to identify PCa aggressiveness biomarkers. The power of the predictive model was further reinforced by ranking the DMPs with Decreased Gini and re-train the model with the top 97 DMPs (Testing AUC=0.920, predict accuracy=0.847). Similar approaches were performed to detect methylation differences between normal and PCa patient leukocyte DNA. Moreover, we analyzed 8 whole genome bisulfite sequencing (WGBS) patient leukocyte DNA specimens from the patient pool with Model based Analysis of Bisulfite Sequencing data (MOABS), an integrated tool for bisulfite sequencing analysis. DNA microarray and WGBS results were highly correlated (r=0.946) and mutual biomarkers were identified. To make MOABS analysis widely accessible, we also utilized bioinformatics methods to implement MOABS to the galaxy platform and validated the power of MOABS-Galaxy with quick test and public bisulfite sequencing datasets. In summary, we identified a CpG methylation signature in leukocyte DNA that is associated with PCa aggressiveness and biochemical recurrence and developed the MOABS-Galaxy web service for DNA methylation analysis using bisulfite sequencing data. Our epigenetic mechanism study may provide an alternative option for PCa screening from epigenetic biomarkers, and implementation of MOABS could benefit biologists from non-computational background on bisulfite sequencing data analysis. | en |
