To develop new methods to distinguish indolent from aggressive prostate cancers (PCa), we utilized comprehensive high-throughput array-based relative methylation (CHARM) assay to identify differentially methylated regions (DMRs) throughout the genome, including both CpG island (CGI) and non-CGI regions in PCa patients based on Gleason grade.
Initially, 26 samples, including eight each of low [Gleason score (GS) 6] and high (GS ≥7) grade PCa samples and ten matched normal prostate tissues, were analyzed as a discovery cohort. We identified 3,567 DMRs between normal and cancer tissues, and 913 DMRs distinguishing low from high-grade cancers. Most of these DMRs were located at CGI shores. The top five candidate DMRs from the low vs. high Gleason comparison, including OPCML, ELAVL2, EXT1, IRX5, and FLRT2, were validated by pyrosequencing using the discovery cohort. OPCML and FLRT2 were further validated in an independent cohort consisting of 20 low-Gleason and 33 high-Gleason tissues. We then compared patients with biochemical recurrence (n=70) versus those without (n=86) in a third cohort, and they showed no difference in methylation at these DMR loci. When GS 3+4 cases and GS 4+3 cases were compared, OPCML-DMR methylation showed a trend of lower methylation in the recurrence group (n=30) than in the no-recurrence (n=52) group. We conclude that whole-genome methylation profiling with CHARM revealed distinct patterns of differential DNA methylation between normal prostate and PCa tissues, as well as between different risk groups of PCa as defined by Gleason scores. A panel of selected DMRs may serve as novel surrogate biomarkers for Gleason score in PCa.
Epigenetics. 2016 Feb 18 [Epub ahead of print]
Yu Wu, Jerry Davison, Xiaoyu Qu, Colm Morrissey, Barry Storer, Lisha Brown, Robert Vessella, Peter Nelson, Min Fang
a Fred Hutchinson Cancer Research Center , Seattle , WA. , a Fred Hutchinson Cancer Research Center , Seattle , WA. , a Fred Hutchinson Cancer Research Center , Seattle , WA. , b University of Washington , Seattle , WA. , a Fred Hutchinson Cancer Research Center , Seattle , WA. , b University of Washington , Seattle , WA. , b University of Washington , Seattle , WA. , a Fred Hutchinson Cancer Research Center , Seattle , WA. , a Fred Hutchinson Cancer Research Center , Seattle , WA.