Abstract
The goal of this retrospective, multicenter study was to evaluate the ability of a newly developed refinement of a quantitative methylation-specific PCR assay to detect prostate cancer in histopathologically negative biopsy samples collected from men who were later positively diagnosed during a follow-up biopsy procedure. Biomarkers tested in the assay included the much-studied glutathione-S-transferase P1 gene and others reported to be frequently methylated in prostate cancer. Core biopsy tissue from subjects with serial negative biopsies served as a negative control to assess assay specificity. As a positive control, biopsy core tissue from patients histopathologically diagnosed with prostate cancer was used to gauge true marker sensitivity in known cancer-containing specimens. Testing was completed in 971 archived paraffin-embedded tissue blocks from 264 men screened for prostate cancer. More samples were initially tested, but due to the advanced age of the paraffinized tissue, DNA quality for quantitative methylation-specific PCR analysis was insufficient in 34% of the available blocks. The glutathione-S-transferase P1 gene has been confirmed as a powerful indicator of the presence of prostate cancer cells. A sensitivity of 52% was observed in the "potentially false-negative first biopsies," with a corresponding specificity of 85% and the sensitivity in biopsy tissue cores containing histopathologically confirmed prostate cancer was 95%. An even higher sensitivity can be reached with RAR-2beta (84%) and APC (72%), with respective specificities of 48% and 50%. Gene methylation was detected in initial, negative biopsy tissue in men who were later diagnosed with prostate cancer. Testing for methylation in histopathologically negative biopsies could improve the early detection of prostate cancer.
Highlights
Prostate cancer remains a major medical health issue representing the most frequent cancer among men
We recognize that a distinction has been made between clinically significant and histologic prostate cancer, our objective was to determine if DNA methylation status would increase the accuracy of the histopathologic diagnosis of prostate cancer
In the population-based, multi-site Prostate Cancer Prevention Trial, repeat biopsy of men enrolled in the placebo arm showed that 22% (1,074/4,921) were positive on first biopsy and 16% (112/687) of men who were negative on a first biopsy were positive on the second [6]
Summary
Prostate cancer remains a major medical health issue representing the most frequent cancer among men. The biopsy process itself, the gold standard for diagnosis, has a false-negative rate as high as 30% and is affected by the number of cores obtained [2, 3]. In this study ∼15% of men with a negative diagnosis after a first set of core biopsies were false negatives. Due to the substantial false-negative rate, needle biopsy of the prostate does not perform well at excluding a cancer diagnosis. The study reported here tested tissue from men with serial prostatic biopsies to determine the utility of quantitative methylation marker testing to meet this objective. Methylation of the glutathione-S-transferase P1 gene (GST-Pi) is associated with loss of expression of this critical DNA-detoxifying protein and has been extensively studied as a marker for prostate cancer [8, 9]. A new refinement of a PCR-based assay has been developed for DNA methylation based on real-time measurement of the fluorescent signal created by the products of the PCR reaction in which the degree of methylation is proportional to the amount of fluorescent product [12, 13]
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