title: Methylation profiling identified novel differentially methylated markers including OPCML and FLRT2 in prostate cancer.
abstract: 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 8 each of low [Gleason score (GS) 6] and high (GS ≥7) grade PCa samples and 10 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 5 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) vs. 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.
authors.affiliation: a Fred Hutchinson Cancer Research Center , Seattle , WA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wu
authors.affiliation: a Fred Hutchinson Cancer Research Center , Seattle , WA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Davison
authors.affiliation: a Fred Hutchinson Cancer Research Center , Seattle , WA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Qu
authors.affiliation: b University of Washington , Seattle , WA.
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
authors.affiliation: a Fred Hutchinson Cancer Research Center , Seattle , WA.
authors.forename: Barry
authors.initials: B
authors.lastname: Storer
authors.affiliation: b University of Washington , Seattle , WA.
authors.forename: Lisha
authors.initials: L
authors.lastname: Brown
authors.affiliation: b University of Washington , Seattle , WA.|c Puget Sound VA Health Care System , Seattle , WA.
authors.forename: Robert
authors.initials: R
authors.lastname: Vessella
authors.affiliation: a Fred Hutchinson Cancer Research Center , Seattle , WA.|b University of Washington , Seattle , WA.
authors.forename: Peter
authors.initials: P
authors.lastname: Nelson
authors.affiliation: a Fred Hutchinson Cancer Research Center , Seattle , WA.|b University of Washington , Seattle , WA.
authors.forename: Min
authors.initials: M
authors.lastname: Fang
mesh_terms: D000328:Adult; D000368:Aged; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D015815:Cell Adhesion Molecules; C404491:FLRT2 protein, human; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C059785:OPCML protein, human
keywords: DMR (differentially methylated regions); methylation profiling; prostate cancer