Discovery and Validation of 3 Novel DNA Methylation Markers of Prostate Cancer Prognosis

No AccessJournal of UrologyAdult urology1 May 2007Discovery and Validation of 3 Novel DNA Methylation Markers of Prostate Cancer Prognosisis accompanied byIdentification of a Recurrent t(4;6) Chromosomal Translocation in Prostate Cancer Susan Cottrell, Klaus Jung, Glen Kristiansen, Elke Eltze, Axel Semjonow, Michael Ittmann, Arndt Hartmann, Thomas Stamey, Carolina Haefliger, and Gunter Weiss Susan CottrellSusan Cottrell Epigenomics, Inc., Seattle, Washington , Klaus JungKlaus Jung University Hospital Charité, Berlin , Glen KristiansenGlen Kristiansen University Hospital Charité, Berlin , Elke EltzeElke Eltze Prostate Center, University of Muenster, Muenster , Axel SemjonowAxel Semjonow Prostate Center, University of Muenster, Muenster , Michael IttmannMichael Ittmann Baylor College of Medicine, Houston, Texas , Arndt HartmannArndt Hartmann Institute of Pathology, University of Regensburg, Regensburg, Germany , Thomas StameyThomas Stamey Stanford University Medical Center, Stanford, California , Carolina HaefligerCarolina Haefliger Epigenomics AG, Berlin , and Gunter WeissGunter Weiss Epigenomics AG, Berlin View All Author Informationhttps://doi.org/10.1016/j.juro.2007.01.010AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: About 15% of men experience prostate specific antigen recurrence after radical prostatectomy. A DNA methylation based molecular test could provide important information to predict which patients are most likely to experience recurrence. Materials and Methods: We performed a genome-wide scan to find aberrantly methylated loci in prostate cancer from patients with early recurrence, high Gleason score or advanced stage. We discovered 441 candidate methylation markers and further analyzed 62 candidates in a methylation microarray study of 304 frozen prostatectomy samples. Results: Methylation of 25 markers was significantly changed in high Gleason score (8–10) vs low Gleason score (2–6) cancers. Methylation levels of the 3 marker candidates GPR7, ABHD9 and an expressed sequence tag on chromosome 3 (Chr3-EST) were significantly increased in patients who did vs did not experience early PSA recurrence (Bonferroni correction p <0.05). Furthermore, these markers were also informative when the sample set was restricted to 68 mid range Gleason score (6 or 7) samples only. We developed real-time polymerase chain reaction assays for ABHD9 and Chr3-EST, and measured methylation in paraffin embedded, formalin fixed prostatectomy samples from an independent set of 223 patients. Methylation of the 2 markers was significantly higher in patients with early PSA recurrence compared to that in patients who did not experience PSA recurrence. Conclusions: We report that methylation of the 3 novel markers GPR7, ABHD9 and Chr3-EST is significantly associated with prostate cancer prognosis. Incorporation of these methylation markers into clinical practice will result in more accurate prediction of which patients are likely to experience PSA recurrence. References 1 : Natural history of progression after PSA elevation following radical prostatectomy. JAMA1999; 281: 1591. Google Scholar 2 : Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: long-term results. J Urol2004; 172: 910. Link, Google Scholar 3 : Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med1999; 341: 1781. Google Scholar 4 : Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program. J Urol2002; 168: 429. Link, Google Scholar 5 : Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the early prostate cancer program at median followup of 5.4 years. J Urol2004; 172: 1865. Link, Google Scholar 6 : When and how to use informatics tools in caring for urologic patients. Nat Clin Pract Urol2005; 2: 183. Google Scholar 7 : Epigenetic heterogeneity of high-grade prostatic intraepithelial neoplasia: clues for clonal progression in prostate carcinogenesis. Mol Cancer Res2006; 4: 1. Google Scholar 8 : Promoter hypermethylation as an independent prognostic factor for relapse in patients with prostate cancer following radical prostatectomy. Clin Cancer Res2005; 11: 8321. Google Scholar 9 : Identification of DNA methylation differences during tumorigenesis by methylation-sensitive arbitrarily primed polymerase chain reaction. Methods2002; 27: 150. Google Scholar 10 : Methylated CpG island amplification for methylation analysis and cloning differentially methylated sequences. Methods Mol Biol2002; 200: 101. Google Scholar 11 : Improved bisulfite conversion of DNA. Alexandria, Virginia: United States Patent and Trademark Office2005. patent PCT/WO/EP/05/038051. Google Scholar 12 : Tumour class prediction and discovery by microarray-based DNA methylation analysis. Nucleic Acids Res2002; 30: e21. Google Scholar 13 : Statistical process control for large scale microarray experiments. Bioinformatics2002; 18: S155. Google Scholar 14 : Association of DNA methylation of phosphoserine aminotransferase with response to endocrine therapy in patients with recurrent breast cancer. Cancer Res2005; 65: 4101. Google Scholar 15 : The Statistical Evaluation of Medical Tests for Classification and Prediction. New York: Oxford University Press USA2003. Google Scholar 16 : Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2′-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci2006; 97: 64. Google Scholar 17 : The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet2001; 27: 159. Google Scholar 18 : Targeted disruption of GPR7, the endogenous receptor for neuropeptides B and W, leads to metabolic defects and adult-onset obesity. Proc Natl Acad Sci U S A2003; 100: 10540. Google Scholar 19 : Neuropeptide B-deficient mice demonstrate hyperalgesia in response to inflammatory pain. Proc Natl Acad Sci U S A2005; 102: 9942. Google Scholar © 2007 by American Urological AssociationFiguresReferencesRelatedDetailsCited ByWeiss G, Cottrell S, Distler J, Schatz P, Kristiansen G, Ittmann M, Haefliger C, Lesche R, Hartmann A, Corman J and Wheeler T (2018) DNA Methylation of the PITX2 Gene Promoter Region is a Strong Independent Prognostic Marker of Biochemical Recurrence in Patients With Prostate Cancer After Radical ProstatectomyJournal of Urology, VOL. 181, NO. 4, (1678-1685), Online publication date: 1-Apr-2009.Related articlesJournal of Urology9 Nov 2018Identification of a Recurrent t(4;6) Chromosomal Translocation in Prostate Cancer Volume 177Issue 5May 2007Page: 1753-1758 Advertisement Copyright & Permissions© 2007 by American Urological AssociationKeywordsprostateDNA methylationprostate-specific antigenmicroarray analysisprostatic neoplasmsMetricsAuthor Information Susan Cottrell Epigenomics, Inc., Seattle, Washington Financial interest and/or other relationship with Epigenomics. More articles by this author Klaus Jung University Hospital Charité, Berlin More articles by this author Glen Kristiansen University Hospital Charité, Berlin More articles by this author Elke Eltze Prostate Center, University of Muenster, Muenster More articles by this author Axel Semjonow Prostate Center, University of Muenster, Muenster Financial interest and/or other relationship with Beckman-Coulter, Hybritech and Biomerieux. More articles by this author Michael Ittmann Baylor College of Medicine, Houston, Texas More articles by this author Arndt Hartmann Institute of Pathology, University of Regensburg, Regensburg, Germany More articles by this author Thomas Stamey Stanford University Medical Center, Stanford, California More articles by this author Carolina Haefliger Epigenomics AG, Berlin Financial interest and/or other relationship with Epigenomics. More articles by this author Gunter Weiss Epigenomics AG, Berlin Financial interest and/or other relationship with Epigenomics. More articles by this author Expand All Advertisement PDF DownloadLoading ...