Abstract
BackgroundActive surveillance (AS) is a promising option for patients with low-risk prostate cancer (PCa), however current criteria could not select the patients correctly, many patients who fulfilled recent AS criteria experienced pathological Gleason score upgrade (PGU) after radical prostatectomy (RP). In this study, we aimed to develop an accurate model for predicting PGU among low-risk PCa patients by using exome genotyping.MethodsWe genotyped 242,221 single nucleotide polymorphisms (SNP)s on a custom HumanExome BeadChip v1.0 (Illuminam Inc.) in blood DNA from 257 low risk PCa patients (PSA <10 ng/ml, biopsy Gleason score (GS) ≤6 and clinical stage ≤T2a) who underwent radical prostatectomy. Genetic data were analyzed using an unconditional logistic regression to calculate an odds ratio as an estimate of relative risk of PGU, which defined pathologic GS above 7. Among them, we selected persistent SNPs after multiple testing using FDR method, and we compared accuracies from the multivariate logistic model incorporating clinical factors between included and excluded selected SNP information.ResultsAfter analysis of exome genotyping, 15 SNPs were significant to predict PGU in low risk PCa patients. Among them, one SNP – rs33999879 remained significant after multiple testing. When a multivariate model incorporating factors in Epstein definition – PSA density, biopsy GS, positive core number, tumor per core ratio and age was devised for the prediction of PGU, the predictive accuracy of the multivariate model was 78.4% (95%CI: 0.726–0.834). By addition the factor of rs33999879 in aforementioned multivariate model, the predictive accuracy was 82.9%, which was significantly increased (p = 0.0196).ConclusionThe rs33999879 SNP is a predictor for PGU. The addition of genetic information from the exome sequencing effectively enhanced the predictive accuracy of the multivariate model to establish suitable active surveillance criteria.
Highlights
Active surveillance (AS) of prostate cancer (PCa) with delayed intervention represents an attractive management option, as it delays and possibly avoids the morbidity and potential mortality associated with radical prostatectomy (RP) or various radiotherapy alternatives [1,2]
Despite the promising results of several major surveillance cohorts, and its 10-year disease specific survival of 97– 100% [3], the estimation of whether patients should be actively treated for low-risk PCa remains controversial, as multiple studies have reported that a considerable proportion of men qualifying for AS have aggressive tumor features at the time of RP [4,5]
The top five associations found for pathological Gleason score upgrade (PGU) were nonsynonymous single nucleotide polymorphisms (SNP): rs33999879 (SMC4, Asn356Ser, odds ratio (OR) = 0.07, P = 5.461027), rs117692893 (KIAA0319, Ser255Thr, OR = 0.16, P = 9.761026), rs641738 (TMC4, Gly17Glu, OR = 0.39, P = 8.161025), and rs4805162 (ZNF565, Thr188Ile, OR = 0.43, P = 9.661025) were negatively correlated with PGU
Summary
Active surveillance (AS) of prostate cancer (PCa) with delayed intervention represents an attractive management option, as it delays and possibly avoids the morbidity and potential mortality associated with radical prostatectomy (RP) or various radiotherapy alternatives [1,2]. As with Epstein’s criteria, the National Comprehensive Cancer Network, (NCCN), defined very low-risk PCa as that with prostate-specific antigen (PSA) ,10 ng/ml, PSA density #0.15 ng/ml/cm, clinical stage #T1c, Gleason score (GS) #6, numbers of positive cores #2, and cancer involvement per core #50% [7,8]. These criteria of very low-risk PCa are currently widely used in the selection of patients for AS [9]. We aimed to develop an accurate model for predicting PGU among low-risk PCa patients by using exome genotyping
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