title: A novel DNA methylation score accurately predicts death from prostate cancer in men with low to intermediate clinical risk factors.
abstract: Clinically aggressive disease behavior is difficult to predict in men with low to intermediate clinical risk prostate cancer and methylation biomarkers may be a valuable adjunct for assessing the management of these patients. We set to evaluate the utility of DNA methylation to identify high risk disease in men currently considered as low or intermediate risk. DNA was extracted from formalin-fixed paraffin-embedded transurethral prostate resection tissues collected during the years 1990-96 in a watchful-waiting cohort of men in the UK. The primary end point was death of prostate cancer, assessed by reviewing cancer registry records from 2009. Methylation was quantified by pyrosequencing assays for six genes (HSPB1, CCND2, TIG1, DPYS, PITX2, and MAL) with established biomarker value in prostate cancer. A novel prognostic methylation score was developed by multivariate Cox modelling using the six methylation biomarkers in 385 men with low-and-intermediate clinical risk variables and its prognostic value compared to two previously defined clinically-derived risk scores. Methylation score was the most significant variable in univariate and bivariate analysis in men with low-to-intermediate CAPRA risk score. When combined with CAPRA score the hazard ratio was 2.02; 95% confidence interval, 1.40-2.92. For a methylation score sensitivity of 83% the specificity was 44%, while the maximum achieved sensitivity by CAPRA was 68% at a specificity of 44%. The derived methylation score is a strong predictor of aggressive prostate cancer that could have an important role in directing the management of patients with low-to-intermediate risk disease. The estimated areas under the curve (AUC) at 10 years of follow-up were 0.62 (95% CI: 0.51, 0.70) and 0.74 (95% CI: 0.65, 0.82) for CAPRA, and combined (CAPRA + methylation) risk score (CRS) respectively.
authors.affiliation: Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK.
authors.forename: Amar S
authors.initials: AS
authors.lastname: Ahmad
authors.affiliation: Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK.
authors.forename: Nataša
authors.initials: N
authors.lastname: Vasiljević
authors.affiliation: Centre for Molecular Pathology, Royal Marsden Hospital, Sutton, SM2 5PT, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Carter
authors.affiliation: Molecular Oncology Centre, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Berney
authors.affiliation: King's College London, Cancer Epidemiology and Population Global Health Program, London, SE1 3QD, UK.
authors.forename: Henrik
authors.initials: H
authors.lastname: Møller
authors.affiliation: HCA International, Pathology Laboratories, London, WC1E 6JA, UK.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Foster
authors.affiliation: Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK.
authors.forename: Jack
authors.initials: J
authors.lastname: Cuzick
authors.affiliation: Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK.
authors.forename: Attila T
authors.initials: AT
authors.lastname: Lorincz
mesh_terms: D019175:DNA Methylation; D006801:Humans; D008297:Male; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D012307:Risk Factors
keywords: CAPRA score; DNA methylation; progression biomarkers; prostate cancer; survival analysis