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DNA methylation in repeat negative prostate biopsies as a marker of missed prostate cancer.

ABSTRACT: BACKGROUND:Men often undergo repeat prostate biopsies because of suspicion of missed cancer. We assessed if (i) methylation of selected genes in prostate tissue vary with aging and (ii) methylation alterations in repeat biopsies predict missed prostate cancer. METHODS:We conducted a case-control study among men who underwent at least two negative prostate biopsies followed by a sampling either positive (cases n = 111) or negative (controls n = 129) for prostate cancer between 1995 and 2014 at the University Hospital (Turin, Italy). Two pathology wards were included for replication purposes. We analyzed methylation of GSTP1, APC, PITX2, C1orf114, GABRE, and LINE-1 in the first two negative biopsies. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of the association between genes methylation and prostate cancer. RESULTS:Age at biopsy and time interval between the two negative biopsies were not associated with methylation levels of the selected genes in neither cases nor controls. GSTP1 methylation in the first and in the second negative biopsy was associated with prostate cancer detection [OR per 1% increase: 1.14 (95% CI 1.01-1.29) for the second biopsy and 1.21 (95% CI 1.07-1.37) for the highest methylation level (first or second biopsy)]. A threshold > 10% for GSTP1 methylation corresponded to a specificity of 0.98 (positive likelihood ratio 7.87). No clear association was found for the other genes. Results were consistent between wards. CONCLUSIONS:Our results suggest that GSTP1 methylation in negative prostate biopsies is stable over time and can predict missed cancer with high specificity.

SUBMITTER: Fiano V

PROVIDER: S-EPMC6820908 | biostudies-other | 2019 Oct

REPOSITORIES: biostudies-other

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DNA methylation in repeat negative prostate biopsies as a marker of missed prostate cancer.

Fiano Valentina V Zugna Daniela D Grasso Chiara C Trevisan Morena M Delsedime Luisa L Molinaro Luca L Cassoni Paola P Papotti Mauro M Merletti Franco F Akre Olof O Pettersson Andreas A De Marco Laura L Richiardi Lorenzo L

Clinical epigenetics 20191030 1

<h4>Background</h4>Men often undergo repeat prostate biopsies because of suspicion of missed cancer. We assessed if (i) methylation of selected genes in prostate tissue vary with aging and (ii) methylation alterations in repeat biopsies predict missed prostate cancer.<h4>Methods</h4>We conducted a case-control study among men who underwent at least two negative prostate biopsies followed by a sampling either positive (cases n = 111) or negative (controls n = 129) for prostate cancer between 1995 ...[more]

PMID: 31666119

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Project description:UnlabelledStudy Type - Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Hypermethylation of genes such as glutathione-S-transferase P1 (GSTP1) and adenomatous polyposis coli (APC) occurs with high frequency in prostate tumour tissue but is much less common in the benign prostate; however, the potential value of gene methylation biomarkers as an adjunct to biopsy histopathology has had little study. When measured in histologically benign prostate biopsy tissue, APC gene hypermethylation was found to have high negative predictive value and high sensitivity. GSTP1 hypermethylation was found to have lower performance than APC.ObjectiveTo evaluate the performance of DNA methylation biomarkers in the setting of repeat biopsy in men with an initially negative prostate biopsy but a high index of suspicion for missed prostate cancer.Patients and methodsWe prospectively evaluated 86 men with an initial histologically negative prostate biopsy and high-risk features. All men underwent repeat 12-core ultrasonography-guided biopsy. DNA methylation of glutathione-S-transferase P1 (GSTP1) and adenomatous polyposis coli (APC) was determined using tissue from the initially negative biopsy and compared with histology of the repeat biopsy. The primary outcome was the relative negative predictive value (NPV) of APC compared with GSTP1, and its 95% confidence interval (CI).ResultsOn repeat biopsy, 21/86 (24%) men had prostate cancer. APC and GSTP1 methylation ratios below the threshold (predicting no cancer) produced a NPV of 0.96 and 0.80, respectively. The relative NPV was 1.2 (95% CI: 1.06-1.36), indicating APC has significantly higher NPV. Methylation ratios above the threshold yielded a sensitivity of 0.95 for APC and 0.43 for GSTP1. Combining both methylation markers produced a performance similar to that of APC alone. APC methylation patterns were consistent with a possible field effect or occurrence early in carcinogenesis.ConclusionsAPC methylation provided a very high NPV with a low percentage of false-negatives, in the first prospective study to evaluate performance of DNA methylation markers in a clinical cohort of men undergoing repeat biopsy. The potential of APC methylation to reduce unnecessary repeat biopsies warrants validation in a larger prospective cohort.

Project description:BackgroundBetter prognostic outcome is closely correlated with early detection of bladder cancer. Current non-invasive urianalysis relies on simultaneously testing multiple methylation markers to achieve relatively high accuracy. Therefore, we have developed an easy-to-use, convenient, and accurate single-target urine-based DNA methylation test for the malignancy.MethodsBy analyzing TCGA data, 344 candidate markers with 424 primer pairs and probe sets synthesized were systematically screened in cancer cell lines, paired tissue specimens, and urine sediments from bladder cancer patients and normal controls. The identified marker was further validated in large case-control cohorts. Wilcoxon rank sum tests and c2 tests were performed to compare methylation levels between case-control groups and correlate methylation levels with demographic and clinical characteristics. In addition, MSP, qMSP, RT-PCR, western blot analysis, and immunohistochemistry were performed to measure levels of DNA methylation, mRNA transcription, and protein expression in cancer cell lines and tissues.ResultsA top-performing DMRTA2 marker identified was tested in both discovery and validation sets, showing similar sensitivity and specificity for bladder cancer detection. Overall sensitivity in the aggregate set was 82.9%(179/216). The specificity, from a control group consisting of patients with lithangiuria, prostatoplasia, and prostatitis, is 92.5%(468/506). Notably, the methylation assay had the highest sensitivities for tumors at stages of T1(90.4%) and T2(95.0%) compared with Ta (63.0%), T3(81.8%), and T4(81.8%). Furthermore, the test showed admirable detection rate of 80.0%(24/30) for recurring cancers. While methylation was observed in 39/54(72.2%) urine samples from patients with carcinomas of renal pelvis and ureter, it was detected at extremely low rate of 6.0%(8/133) in kidney and prostate cancers. Compared with SV-HUC-1, the normal bladder epithelial cell line, DMRTA2 was hypermethylated in 8/9 bladder cancer cell lines, consistent with the results of MSP and qMSP, but not correlated with mRNA and protein expression levels in these cell lines. Similarly, DMRTA2 immunostaining was moderate in some tissues but weak in others. Further studies are needed to address functional implications of DMRTA2 hypermethylation.ConclusionsOur data demonstrated that a single-target DNA methylation signature, mDMRTA2, could be highly effective to detect both primary and recurring bladder cancer via urine samples.

Project description:BackgroundOur objective was to develop and validate a multi-feature nuclear score based on image analysis of direct DNA staining, and to test its association with field effects and subsequent detection of prostate cancer (PCa) in benign biopsies.MethodsTissue sections from 39 prostatectomies were Feulgen-stained and digitally scanned (400×), providing maps of DNA content per pixel. PCa and benign epithelial nuclei were randomly selected for measurement of 52 basic morphometric features. Logistic regression models discriminating benign from PCa nuclei, and benign from malignant nuclear populations, were built and cross-validated by AUC analysis. Nuclear populations were randomly collected <1 mm or >5 mm from cancer foci, and from cancer-free prostates, HGPIN, and PCa Gleason grade 3-5. Nuclei also were collected from negative biopsy subjects who had a subsequent diagnosis of PCa and age-matched cancer-free controls (20 pairs).ResultsA multi-feature nuclear score discriminated cancer from benign cell populations with AUCs of 0.91 and 0.79, respectively, in training and validation sets of patients. In prostatectomy samples, both nuclear- and population-level models revealed cancer-like features in benign nuclei adjacent to PCa, compared to nuclei that were more distant or from PCa-free glands. In negative biopsies, a validated model with 5 variance features yielded significantly higher scores in cases than controls (P = 0.026).ConclusionsA multifeature nuclear morphometric score, obtained by automated digital analysis, was validated for discrimination of benign from cancer nuclei. This score demonstrated field effects in benign epithelial nuclei at varying distance from PCa lesions, and was associated with subsequent PCa detection in negative biopsies.ImpactThis nuclear score shows promise as a risk predictor among men with negative biopsies and as an intermediate biomarker in Phase II chemoprevention trials. The results also suggest that subvisual disturbances in nuclear structure precede the development of pre-neoplastic lesions.

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DNA methylation in repeat negative prostate biopsies as a marker of missed prostate cancer.

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DNA methylation in repeat negative prostate biopsies as a marker of missed prostate cancer.

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