A novel DNA methylation score accurately predicts death from prostate cancer in men with low to intermediate clinical risk factors
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Amar S. Ahmad1, Nataša Vasiljević1, Paul Carter2, Daniel M Berney3, Henrik Møller4, Christopher S. Foster5, Jack Cuzick1, Attila T. Lorincz1
1Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK
2Centre for Molecular Pathology, Royal Marsden Hospital, Sutton, SM2 5PT, UK
3Molecular Oncology Centre, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
4King’s College London, Cancer Epidemiology and Population Global Health Program, London, SE1 3QD, UK
5HCA International, Pathology Laboratories, London, WC1E 6JA, UK
Attila T. Lorincz, email: [email protected]
Keywords: prostate cancer, progression biomarkers, DNA methylation, CAPRA score, survival analysis
Received: August 12, 2016 Accepted: September 20, 2016 Published: September 30, 2016
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.
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