Noninvasive Detection of High Grade Prostate Cancer by DNA Methylation Analysis of Urine Cells Captured by Microfiltration

Larsen, Louise Katrine; Jakobsen, Jørn Skibsted; Abdul-Al, Ahmad; Guldberg, Per

doi:10.1016/j.juro.2018.04.067

Cited by 17 publications

(21 citation statements)

References 21 publications

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“…Another approach to increase the sensitivity is repeated urine sampling. In a study of men with high-grade prostate cancer, analysis of urine cells collected by filtration on different days without prior DRE showed a great interday variation in the presence of DNA methylation biomarkers, with some samples giving a false-negative result [49]. A study of patients with small low-grade bladder tumors showed that analysis of pooled urine samples collected over 24 h resulted in a sensitivity of 100%, whereas it was only 75% when a single urine sample was analyzed [50].…”

Section: Factors Affecting Biomarker Performancementioning

confidence: 99%

DNA-Methylation-Based Detection of Urological Cancer in Urine: Overview of Biomarkers and Considerations on Biomarker Design, Source of DNA, and Detection Technologies

Larsen

Lind

Guldberg

et al. 2019

IJMS

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Changes in DNA methylation have been causally linked with cancer and provide promising biomarkers for detection in biological fluids such as blood, urine, and saliva. The field has been fueled by genome-wide characterization of DNA methylation across cancer types as well as new technologies for sensitive detection of aberrantly methylated DNA molecules. For urological cancers, urine is in many situations the preferred “liquid biopsy” source because it contains exfoliated tumor cells and cell-free tumor DNA and can be obtained easily, noninvasively, and repeatedly. Here, we review recent advances made in the development of DNA-methylation-based biomarkers for detection of bladder, prostate, renal, and upper urinary tract cancers, with an emphasis on the performance characteristics of biomarkers in urine. For most biomarkers evaluated in independent studies, there was great variability in sensitivity and specificity. We discuss issues that impact the outcome of DNA-methylation-based detection of urological cancer and account for the great variability in performance, including genomic location of biomarkers, source of DNA, and technical issues related to the detection of rare aberrantly methylated DNA molecules. Finally, we discuss issues that remain to be addressed to fully exploit the potential of DNA-methylation-based biomarkers in the clinic, including the need for prospective trials and careful selection of control groups.

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Section: Factors Affecting Biomarker Performancementioning

confidence: 99%

DNA-Methylation-Based Detection of Urological Cancer in Urine: Overview of Biomarkers and Considerations on Biomarker Design, Source of DNA, and Detection Technologies

Larsen

Lind

Guldberg

et al. 2019

IJMS

Self Cite

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“…It is critical that urine used for analysis of nucleic acids is immediately processed with a preservative after collection. Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) is the most commonly used method for measuring expression of candidate markers, but analytical protocols for transcript quantification vary between studies with some report performing cDNA preamplification [66, 68], while others do not [69], and some use transcription-mediated amplification (TMA) [60, 70] or droplet digital PCR (ddPCR) [71]. Additionally, lack of consistent urine sampling and processing procedures exists across different studies.…”

Section: Nucleic Acid Biomarkersmentioning

confidence: 99%

Approaches to urinary detection of prostate cancer

Eskra

Rabizadeh

Pavlovich

et al. 2019

Prostate Cancer Prostatic Dis

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Background: Prostate cancer is the most common cancer in American men that ranges from low risk states amenable to active surveillance to high risk states that can be lethal especially if untreated. There is a critical need to develop relatively non-invasive and clinically useful methods for screening, detection, prognosis, disease monitoring, and prediction of treatment efficacy. In this review, we focus on important advances as well as future efforts needed to drive clinical innovation in this area of urine biomarker research for prostate cancer detection and prognostication. Methods: We provide a review of current literature on urinary biomarkers for prostate cancer. We evaluate the strengths and limitations of a variety of approaches that vary in sampling strategies and targets measured; discuss reported urine tests for prostate cancer with respect to their technical, analytical, and clinical parameters; and provide our perspectives on critical considerations in approaches to developing a urine-based test for prostate cancer. Results: There has been an extensive history of exploring urine as a source of biomarkers for prostate cancer that has resulted in a variety of urine tests that are in current clinical use. Importantly, at least three tests have demonstrated high sensitivity (~90%) and negative predictive value (~95%) for clinically significant tumors; however, there has not been widespread adoption of these tests. Conclusions: Conceptual and methodological advances in the field will help to drive the development of novel urinary tests that in turn may lead to a shift in the clinical paradigm for prostate cancer diagnosis and management.

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“…In our previous study [ 24 ], we histopathologically evaluated inflammation in needle biopsies of BPH. Based on a preliminary analysis, we reported that prostatic inflammation may affect urine PCA3 [ 13 ]. This observation was confirmed in the present study where both PCA3 ( p = 0.041) and serum PSA ( p = 0.005) were significantly increased in patients with inflammation ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…In addition to urine tests and the blood Prostate Health Index or 4KScore, magnetic resonance imaging (MRI) is also an important option [ 5 , 6 , 7 , 8 , 9 , 10 ]. Novel approaches are being tested too, e.g., DNA methylation assays, miRNAs and lncRNAs [ 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

The Percentage of Free PSA and Urinary Markers Distinguish Prostate Cancer from Benign Hyperplasia and Contribute to a More Accurate Indication for Prostate Biopsy

et al. 2020

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The main advantage of urinary biomarkers is their noninvasive character and the ability to detect multifocal prostate cancer (CaP). We have previously implemented a quadruplex assay of urinary markers into clinical practice (PCA3, AMACR, TRPM8 and MSMB with KLK3 normalization). In this study, we aimed to validate it in a larger cohort with serum PSA 2.5–10 ng/mL and test other selected transcripts and clinical parameters, including the percentage of free prostate-specific antigen (PSA) (% free PSA) and inflammation. In the main cohort of 299 men, we tested the quadruplex transcripts. In a subset of 146 men, we analyzed additional transcripts (CD45, EPCAM, EZH2, Ki67, PA2G4, PSGR, RHOA and TBP). After a prostate massage, the urine was collected, RNA isolated from a cell sediment and qRT-PCR performed. Ct values of KLK3 (i.e., PSA) were strongly correlated with Ct values of other genes which play a role in CaP (i.e., PCA3, AMACR, TRPM8, MSMB and PSGR). AMACR, PCA3, TRPM8 and EZH2 mRNA expression, as well as % free PSA, were significantly different for BPH and CaP. The best combined model (% free PSA plus PCA3 and AMACR) achieved an AUC of 0.728 in the main cohort. In the subset of patients, the best AUC 0.753 was achieved for the combination of PCA3, % free PSA, EPCAM and PSGR. PCA3 mRNA was increased in patients with inflammation, however, this did not affect the stratification of patients indicated for prostate biopsy. In conclusion, the percentage of free PSA and urinary markers contribute to a more accurate indication for prostate biopsy.

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Noninvasive Detection of High Grade Prostate Cancer by DNA Methylation Analysis of Urine Cells Captured by Microfiltration

Abstract: Capturing cells from urine by microfiltration provides a novel tool to detect prostate cancer noninvasively with high sensitivity for high grade disease. Repeat sampling may increase sensitivity, particularly when urine is obtained without prior physical manipulation of the prostate.

Cited by 17 publications

References 21 publications

DNA-Methylation-Based Detection of Urological Cancer in Urine: Overview of Biomarkers and Considerations on Biomarker Design, Source of DNA, and Detection Technologies

DNA-Methylation-Based Detection of Urological Cancer in Urine: Overview of Biomarkers and Considerations on Biomarker Design, Source of DNA, and Detection Technologies

Approaches to urinary detection of prostate cancer

The Percentage of Free PSA and Urinary Markers Distinguish Prostate Cancer from Benign Hyperplasia and Contribute to a More Accurate Indication for Prostate Biopsy

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