Dataset Information

MYC DNA Methylation in Prostate Tumor Tissue Is Associated with Gleason Score.

ABSTRACT: Increasing evidence suggests a role of epigenetic mechanisms at chromosome 8q24, an important cancer genetic susceptibility region, in prostate cancer. We investigated whether MYC DNA methylation at 8q24 (six CpG sites from exon 3 to the 3' UTR) in prostate tumor was associated with tumor aggressiveness (based on Gleason score, GS), and we incorporated RNA expression data to investigate the function. We accessed radical prostatectomy tissue for 50 Caucasian and 50 African American prostate cancer patients at the University of Maryland Medical Center, selecting an equal number of GS 6 and GS 7 cases per group. MYC DNA methylation was lower in tumor than paired normal prostate tissue for all six CpG sites (median difference: -14.74 to -0.20 percentage points), and we observed similar results for two nearby sites in The Cancer Genome Atlas (p < 0.0001). We observed significantly lower methylation for more aggressive (GS 7) than less aggressive (GS 6) tumors for three exon 3 sites (for CpG 212 (chr8:128753145), GS 6 median = 89.7%; GS 7 median = 85.8%; p-value = 9.4 × 10^-4). MYC DNA methylation was not associated with MYC expression, but was inversely associated with PRNCR1 expression after multiple comparison adjustment (q-value = 0.04). Findings suggest that prostate tumor MYC exon 3 hypomethylation is associated with increased aggressiveness.

SUBMITTER: Barry KH

PROVIDER: S-EPMC7823928 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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<i>MYC</i> DNA Methylation in Prostate Tumor Tissue Is Associated with Gleason Score.

Barry Kathryn Hughes KH Mohanty Kareshma K Erickson Patricia A PA Wang Difei D Shi Jianxin J Rose Gary G Cellini Ashley A Clark Kimberly K Ambulos Nicholas N Yin Jing J Yan Liying L Poulin Matthew M Meyer Ann A Zhang Yuji Y Bentzen Søren M SM Burke Allen A Hussain Arif A Berndt Sonja I SI

Genes 20201224 1

Increasing evidence suggests a role of epigenetic mechanisms at chromosome 8q24, an important cancer genetic susceptibility region, in prostate cancer. We investigated whether <i>MYC</i> DNA methylation at 8q24 (six CpG sites from exon 3 to the 3' UTR) in prostate tumor was associated with tumor aggressiveness (based on Gleason score, GS), and we incorporated RNA expression data to investigate the function. We accessed radical prostatectomy tissue for 50 Caucasian and 50 African American prostat ...[more]

PMID: 33374332

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Project description:BackgroundProstate tumor volume predicts biochemical recurrence, metastases, and tumor proliferation. A recent study showed that prostate tumor eccentricity (elongation or roundness) correlated with Gleason score. No studies examined the relationship among the prostate tumor's shape, volume, and potential aggressiveness.MethodsOf the 26 patients that were analyzed, 18 had volumes >1 cc for the histology-based study, and 25 took up contrast material for the MRI portion of this study. This retrospective study quantitatively compared tumor eccentricity and volume measurements from pathology assessment sectioned wholemount prostates and multi-parametric MRI to Gleason scores. Multi-parametric MRI (T1, T2, diffusion, dynamic contrast-enhanced images) were resized, translated, and stitched to form spatially registered multi-parametric cubes. Multi-parametric signatures that characterize prostate tumors were inserted into a target detection algorithm (Adaptive Cosine Estimator, ACE). Various detection thresholds were applied to discriminate tumor from normal tissue. Pixel-based blobbing, and labeling were applied to digitized pathology slides and threshold ACE images. Tumor volumes were measured by counting voxels within the blob. Eccentricity calculation used moments of inertia from the blobs.ResultsFrom wholemount prostatectomy slides, fitting two sets of independent variables, prostate tumor eccentricity (largest blob eccentricity, weighted eccentricity, filtered weighted eccentricity) and tumor volume (largest blob volume, average blob volume, filtered average blob volume) to Gleason score in a multivariate analysis, yields correlation coefficient R=0.798 to 0.879 with P<0.01. The eccentricity t-statistic exceeded the volume t-statistic. Fitting histology-based total prostate tumor volume against Gleason score yields R=0.498, P=0.0098. From multi-parametric MRI, the correlation coefficient R between the Gleason score and the largest blob eccentricity for varying thresholds (0.30 to 0.55) ranged from -0.51 to -0.672 (P<0.01). For varying thresholds (0.60 to 0.80) for MRI detection, the R between the largest blob volume eccentricity against the Gleason score ranged from 0.46 to 0.50 (P<0.03). Combining tumor eccentricity and tumor volume in multivariate analysis failed to increase Gleason score prediction.ConclusionsProstate tumor eccentricity, determined by histology or MRI, more accurately predicted Gleason score than prostate tumor volume. Combining tumor eccentricity with volume from histology-based analysis enhanced Gleason score prediction, unlike MRI.

Project description:BackgroundDNA methylation has been hypothesized as a mechanism for explaining the association between smoking and adverse prostate cancer (PCa) outcomes. This study was aimed at assessing whether smoking is associated with prostate tumor DNA methylation and whether these alterations may explain in part the association of smoking with PCa recurrence and mortality.MethodsA total of 523 men had radical prostatectomy as their primary treatment, detailed smoking history data, long-term follow-up for PCa outcomes, and tumor tissue profiled for DNA methylation. Ninety percent of the men also had matched tumor gene expression data. A methylome-wide analysis was conducted to identify differentially methylated regions (DMRs) by smoking status. To select potential functionally relevant DMRs, their correlation with the messenger RNA (mRNA) expression of corresponding genes was evaluated. Finally, a smoking-related methylation score based on the top-ranked DMRs was created to assess its association with PCa outcomes.ResultsForty DMRs were associated with smoking status, and 10 of these were strongly correlated with mRNA expression (aldehyde oxidase 1 [AOX1], claudin 5 [CLDN5], early B-cell factor 1 [EBF1], homeobox A7 [HOXA7], lectin galactoside-binding soluble 3 [LGALS3], microtubule-associated protein τ [MAPT], protocadherin γ A [PCDHGA]/protocadherin γ B [PCDHGB], paraoxonase 3 [PON3], synaptonemal complex protein 2 like [SYCP2L], and zinc finger and SCAN domain containing 12 [ZSCAN12]). Men who were in the highest tertile for the smoking-methylation score derived from these DMRs had a higher risk of recurrence (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.42-3.72) and lethal disease (OR, 4.21; 95% CI, 1.65-11.78) in comparison with men in the lower 2 tertiles.ConclusionsThis integrative molecular epidemiology study supports the hypothesis that smoking-associated tumor DNA methylation changes may explain at least part of the association between smoking and adverse PCa outcomes. Future studies are warranted to confirm these findings and understand the implications for improving patient outcomes. Cancer 2016;122:2168-77. © 2016 American Cancer Society.

Dataset Information

MYC DNA Methylation in Prostate Tumor Tissue Is Associated with Gleason Score.

Publications

<i>MYC</i> DNA Methylation in Prostate Tumor Tissue Is Associated with Gleason Score.

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