DNA methylation status is more reliable than gene expression at detecting cancer in prostate biopsy

Abstract

Background:We analysed critically the potential usefulness of RNA- and DNA-based biomarkers in supporting conventional histological diagnostic tests for prostate carcinoma (PCa) detection.Methods:Microarray profiling of gene expression and DNA methylation was performed on 16 benign prostatic hyperplasia (BPH) and 32 cancerous and non-cancerous prostate samples extracted by radical prostatectomy. The predictive value of the selected biomarkers was validated by qPCR-based methods using tissue samples extracted from the 58 prostates and, separately, using 227 prostate core biopsies.Results:HOXC6, AMACR and PCA3 expression showed the best discrimination between PCa and BPH. All three genes were previously reported as the most promising mRNA-based markers for distinguishing cancerous lesions from benign prostate lesions; however, none were sufficiently sensitive and specific to meet the criteria for a PCa diagnostic biomarker. By contrast, DNA methylation levels of the APC, TACC2, RARB, DGKZ and HES5 promoter regions achieved high discriminating sensitivity and specificity, with area under the curve (AUCs) reaching 0.95−1.0. Only a small overlap was detected between the DNA methylation levels of PCa-positive and PCa-negative needle biopsies, with AUCs ranging between 0.854 and 0.899.Conclusions:DNA methylation-based biomarkers reflect the prostate malignancy and might be useful in supporting clinical decisions for suspected PCa following an initial negative prostate biopsy.

What Can Be Expected from Prostate Cancer Biomarkers A Clinical Perspective

“…Although ConfirmMDx aims mainly at identifying significant PCa by improving sensitivity of detection, DNA methylation assays might also be a valuable tool to distinguish PCa from BPH. In the study by Paziewska et al [85], DNA methylation levels of APC, TACC2, RARB, DGKZ and HES5 promoter regions provided an excellent discrimination between malignant and benign tissues with AUC reaching 0.95-1. Interestingly, in the same study, standard analysis of gene expression of the best 3 genes (HOXC6, AMACR, and PCA3) yielded only moderate accuracy with AUC >0.8 [85].…”

“…In the study by Paziewska et al [85], DNA methylation levels of APC, TACC2, RARB, DGKZ and HES5 promoter regions provided an excellent discrimination between malignant and benign tissues with AUC reaching 0.95-1. Interestingly, in the same study, standard analysis of gene expression of the best 3 genes (HOXC6, AMACR, and PCA3) yielded only moderate accuracy with AUC >0.8 [85]. Simultaneously with growing interest in invasive epigenetic assays, non-invasive methylation biomarkers were evaluated.…”

On the Multiscale Nature of Human Prostate Cancer

“…Today, a new generation of biomarkers is emerging, consisting of serum-, urine-, and tissue-based assays that may supplement PSA testing, or replace it over time [3]. Diagnostic biomarkers should be sensitive and specific enough to show whether disease is present; however, the levels of most biomarkers overlap between tumor and normal tissues [4]. Consequently, it remains difficult to identify an ideal biomarker with enough discriminatory power for an accurate diagnosis of prostate cancer [4].…”

“…Diagnostic biomarkers should be sensitive and specific enough to show whether disease is present; however, the levels of most biomarkers overlap between tumor and normal tissues [4]. Consequently, it remains difficult to identify an ideal biomarker with enough discriminatory power for an accurate diagnosis of prostate cancer [4]. Histological evaluation remains the gold standard.…”

“…The parameter "time"" depends on a large number of variables that are non-linearly interconnected in a multitude of ways, thus making it extremely difficult to predict the exact time interval between two successive states [13]. It has been showed that the decisive step in prostate carcinogenesis is the result of an irreversible qualitative change in one or more of the genetic characteristics of cancer cells, and that tumors have somatic mutations and epigenetic changes [4,14].…”