Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Larsen LK

PROVIDER: S-EPMC6600406 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Larsen Louise Katrine LK Lind Guro Elisabeth GE Guldberg Per P Dahl Christina C

International journal of molecular sciences 20190530 11

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-fre ...[more]

PMID: 31151158

Similar Datasets

Project description:BackgroundProstate cancer (PC) is a multifocal disease. DNA methylation alterations are not restricted to the immediate peritumor environment, but spatially widespread in the adjacent and distant histologically normal prostate tissues. In the current study, we utilized high-throughput methylation arrays to identify epigenetic changes in the urine from men with and without cancer.Design, setting, and participantsDNA urine samples were enriched for methylated fragments using MBD methyl-binding antibodies and applied to high density CytoScanHD arrays. Significant loci were validated using quantitative pyrosequencing and binary logistic regression modeling applied to urine sample analyses in a training (n = 83) and validation approach (n = 84). Methylation alterations in prostate tissues using pyrosequencing at the PLA2G16 locus were examined in 38 histologically normal specimens from men with (TA, n = 26) and without (NTA, n = 12) cancer and correlated to gene expression.ResultsMethylation microarrays identified 3,986 loci showing significantly altered methylation in the urine samples from patients with PC compared to those without (TA vs NTA; p<0.01). These loci were then compared against subjects with their prostates removed to exclude non-prostate cell markers yielding 196 significant regions. Multiple CpGs adjacent to PLA2G16 CpG island showed increased methylation in TA compared to NTA (p<0.01) in a large validation study of urine samples. The predictive accuracy of PLA2G16 methylation at CG2 showed the highest predictive value at 0.8 (odds ratio, 1.37; 95% confidence interval, 1.16-1.62; p<0.001). Using a probability cutoff of 0.065, the sensitivity and specificity of the multivariate model was 92% and 35%. When histologically normal prostate tissues/biopsies from patients with PC (TA) were compared to subjects without cancer, significant hypermethylation of PLA2G16 was noted (odds ratio, 1.35; 95% confidence interval, 1.07-1.71; p = 0.01).ConclusionPLA2G16 methylation defines an extensive field defect in histologically normal prostate tissue associated with PC. PLA2G16 methylation in urine and prostate tissues can detect the presence of PC.

Project description:BackgroundProstate cancer diagnosis using the PSA test remains controversial because of overdiagnosis and overtreatment of potentially indolent cancers. There remains a need to increase the diagnostic lead time and to target treatment to patients with significant disease. One possible approach to overcome the limitations of PSA is to screen men for the molecular signature of early PCA, monitor the rate of disease progression and target treatment to patients who are likely to benefit from it. Such an approach requires a large panel of markers that define a molecular clock for PCA. We recently developed a panel of 19 markers for the non-invasive detection of PCA from urine DNA. It raised the possibility that additional methylation markers could be successfully analyzed from urine DNA, a prerequisite for increasing the diagnostic lead time and enabling disease monitoring.MethodsWe developed semi-quantitative polymerase chain reaction assays for 13 additional markers and determined their methylation status in 150 urine DNAs from 94 patients with elevated PSA. Eighty five samples were obtained following DRE and 65 samples were from first void. We combined the data of the 13 new markers with the previously reported 19 markers and calculated the sensitivity, specificity, negative and positive predictive values at every threshold from one to 32 positive markers.ResultsUsing 10of32 positive markers as the threshold to recommend a biopsy yields a sensitivity of 81% (95% CI 0.68-0.93) and 93% (95% CI 0.84-1.02) and a specificity of 76% (95% CI 0.63-0.88) and 77% (95% CI 0.63-0.91) from DRE and FV DNA, respectively. The PPV was 71% and 77% and the NPV was 85% and 93% from DRE and FV, respectively.ConclusionsThis study shows that large marker panels can be analyzed from urine DNA without loss of sensitivity or specificity. Using 32 markers improved the stratification of patients undergoing screening for PCA particularly for patients below the 10of32 threshold. The results show the utility of larger biomarker panels for PCA diagnosis and suggest that the development of the panels needed to monitor disease progression could be successfully accomplished.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets