Urinary DNA methylation biomarkers for prediction of prostate cancer upgrading and upstaging

Abstract

Background Significant numbers of prostate cancer (PCa) patients experience tumour upstaging and upgrading in surgical specimens that cause serious problems in timely and proper selection of the treatment strategy. This study was aimed at the evaluation of a set of established epigenetic biomarkers as a noninvasive tool for more accurate PCa categorization before radical prostatectomy (RP). Methods Quantitative methylation-specific PCR was applied for the methylation analysis of RARB , RASSF1 , and GSTP1 in 514 preoperatively collected voided or catheterized urine samples from the single-centre cohort of 1056 treatment-naïve PCa patients who underwent RP. The rates of biopsy upgrading and upstaging were analysed in the whole cohort. Results Pathological examination of RP specimens revealed Gleason score upgrading in 27.2% and upstaging in 20.3% of the patients with a total misclassification rate of 39.0%. DNA methylation changes in at least one gene were detected in more than 80% of urine samples. Combination of the PSA test with the three-gene methylation analysis in urine was a significant predictor of pathological upstaging and upgrading ( P < 0.050), however, with limited increase in overall accuracy. The PSA test or each gene alone was not informative enough. Conclusions The urinary DNA methylation assay in combination with serum PSA may predict tumour stage or grade migration post-RP aiding in improved individual risk assessment and appropriate treatment selection. Clinical utility of these biomarkers should be proven in larger multi-centre studies. Electronic supplementary material The online version of this article (10.1186/s13148-019-0716-z) contains supplementary material, which is available to authorized users.

The Impact of Prostate Cancer Upgrading and Upstaging on Biochemical Recurrence and Cancer-Specific Survival

“…Discrepancies between prostate biopsy results and final pathological assessment of prostatectomy specimens may be attributed to diagnostic problems, especially when a higher Gleason grade tumour is missed on the needle biopsy or insufficient biopsy material is available for pathological examination [17]. In the present study, as in our previous research with a larger cohort [7], upgrading and upstaging have been observed in 29% and 22% of PCa patients, respectively.…”

“…Several nomograms have been suggested to predict the probability of pathologic upgrading in patients with low-risk disease [25][26][27], however most of them are based on randomised biopsies and have limited value in counselling patients who are candidates for definitive therapy. Novel molecular biomarkers and genomic classifiers, containing molecular information from all tumour foci and reflecting PCa heterogeneity, have shown accuracy in predicting PCa aggressiveness and may provide valuable information for improved diagnostics [7,[28][29][30].…”

“…In the present study treatment-naïve patients with histologically confirmed localised PCa (≥ 10-core systematic biopsies by transrectal approach) who underwent open RP at Vilnius University Hospital Santaros Klinikos between January 2008 and December 2014 were included. This subgroup is a part of a large cohort involved in the biomarker-based upgrading and upstaging study [7], with available post-operative follow-up. The metastatic disease of intermediate and high-risk PCa was excluded by bone-scan and computer tomography preoperatively.…”

“…Gleason score was evaluated according to the 2005 Guidelines of International Society of Urological Pathology (ISUP) and ISUP grade groups were assigned according to ISUP 2014 recommendations [8,9]. As defined previously [7], upgrading was considered when any increase of ISUP grade group between prostate biopsy (cISUP) and RP pathology (pISUP) was detected, whereas upstaging was confirmed if a patient was pathologically diagnosed with advanced disease (≥pT3) when clinically unsuspected. PSM was defined as the presence of tumour cells at the inked margin on the inspection under microscopy [10].…”

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

“…The epigenetic background of PCa is very diverse [130]. Several gene promoters are consistently found to be hypermethylated in PCa, including for instance GSTP1, which can be detected in several bodily fluids, including plasma or urine [131][132][133][134]. Also, several microRNAs are involved in disease progression and aggressiveness [135,136].…”