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.
Highlights
Current inability to distinguish biologically indolent prostate cancer from that which will progress poses the greatest problem when deciding appropriate clinical management strategies for this disease
Schoenfeld residuals demonstrated no violation of the assumption of proportional hazards in any tested variable, a multivariate Cox proportional hazards model was fitted with the six genes in the 385 men with low-intermediate-risk CAPRA scores
The methylation score was the strongest predictor of prostate cancer related death with a hazard ratio [HR] 2.72, p < 10−8 compared to the CAPRA score HR 1.62, p < 10−7 (Table 1)
Summary
Current inability to distinguish biologically indolent prostate cancer from that which will progress poses the greatest problem when deciding appropriate clinical management strategies for this disease. Prostate cancer patients are commonly categorized as low, intermediate, and high risk to aid management decisions. Tools such as CAPRA (Cancer of the Prostate Risk Assessment) score, [3] which combines baseline PSA level, Gleason score, age, and other clinical variables can provide some qualitative measure of a patient’s risk for progression. A pressing need still exists to validate additional scores for clinical use as well as identify standardized quantifiable molecular biomarker assays, or optimal combinations of biomarkers to improve disease stratification and subsequent management
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