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Unbiased data mining identifies cell cycle transcripts that predict non-indolent Gleason score 7 prostate cancer.

ABSTRACT: BACKGROUND:Patients with newly diagnosed non-metastatic prostate adenocarcinoma are typically classified as at low, intermediate, or high risk of disease progression using blood prostate-specific antigen concentration, tumour T category, and tumour pathological Gleason score. Classification is used to both predict clinical outcome and to inform initial management. However, significant heterogeneity is observed in outcome, particularly within the intermediate risk group, and there is an urgent need for additional markers to more accurately hone risk prediction. Recently developed web-based visualization and analysis tools have facilitated rapid interrogation of large transcriptome datasets, and querying broadly across multiple large datasets should identify predictors that are widely applicable. METHODS:We used camcAPP, cBioPortal, CRN, and NIH NCI GDC Data Portal to data mine publicly available large prostate cancer datasets. A test set of biomarkers was developed by identifying transcripts that had: 1) altered abundance in prostate cancer, 2) altered expression in patients with Gleason score 7 tumours and biochemical recurrence, 3) correlation of expression with time until biochemical recurrence across three datasets (Cambridge, Stockholm, MSKCC). Transcripts that met these criteria were then examined in a validation dataset (TCGA-PRAD) using univariate and multivariable models to predict biochemical recurrence in patients with Gleason score 7 tumours. RESULTS:Twenty transcripts met the test criteria, and 12 were validated in TCGA-PRAD Gleason score 7 patients. Ten of these transcripts remained prognostic in Gleason score 3?+?4?=?7, a sub-group of Gleason score 7 patients typically considered at a lower risk for poor outcome and often not targeted for aggressive management. All transcripts positively associated with recurrence encode or regulate mitosis and cell cycle-related proteins. The top performer was BUB1, one of four key MIR145-3P microRNA targets upregulated in hormone-sensitive as well as castration-resistant PCa. SRD5A2 converts testosterone to its more active form and was negatively associated with biochemical recurrence. CONCLUSIONS:Unbiased mining of large patient datasets identified 12 transcripts that independently predicted disease recurrence risk in Gleason score 7 prostate cancer. The mitosis and cell cycle proteins identified are also implicated in progression to castration-resistant prostate cancer, revealing a pivotal role for loss of cell cycle control in the latter.

SUBMITTER: Johnston WL

PROVIDER: S-EPMC6322345 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Unbiased data mining identifies cell cycle transcripts that predict non-indolent Gleason score 7 prostate cancer.

Johnston Wendy L WL Catton Charles N CN Swallow Carol J CJ

BMC urology 20190107 1

<h4>Background</h4>Patients with newly diagnosed non-metastatic prostate adenocarcinoma are typically classified as at low, intermediate, or high risk of disease progression using blood prostate-specific antigen concentration, tumour T category, and tumour pathological Gleason score. Classification is used to both predict clinical outcome and to inform initial management. However, significant heterogeneity is observed in outcome, particularly within the intermediate risk group, and there is an u ...[more]

PMID: 30616540

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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:BackgroundRadiologists currently subjectively examine multi-parametric magnetic resonance imaging (MRI) to detect possible clinically significant lesions using the Prostate Imaging Reporting and Data System (PI-RADS) protocol. The assessment of imaging, however, relies on the experience and judgement of radiologists creating opportunity for inter-reader variability. Quantitative metrics, such as z-score and signal to clutter ratio (SCR), are therefore needed.MethodsMulti-parametric MRI (T1, T2, diffusion, dynamic contrast-enhanced images) were resampled, rescaled, translated, and stitched to form spatially registered multi-parametric cubes for patients undergoing radical prostatectomy. Multi-parametric signatures that characterize prostate tumors were inserted into z-score and SCR. The multispectral covariance matrix was computed for the outlined normal prostate. The z-score from each MRI image was computed and summed. To reduce noise in the covariance matrix, following matrix decomposition, the noisy eigenvectors were removed. Also, regularization and modified regularization was applied to the covariance matrix by minimizing the discrimination score. The filtered and regularized covariance matrices were inserted into the SCR calculation. The z-score and SCR were quantitatively compared to Gleason scores from clinical pathology assessment of the histology of sectioned wholemount prostates.ResultsTwenty-six consecutive patients were enrolled in this retrospective study. Median patient age was 60 years (range, 49 to 75 years), median prostate-specific antigen (PSA) was 5.8 ng/mL (range, 2.3 to 23.7 ng/mL), and median Gleason score was 7 (range, 6 to 9). A linear fit of the summed z-score against Gleason score found a correlation of R=0.48 and a P value of 0.015. A linear fit of the SCR from regularizing covariance matrix against Gleason score found a correlation of R=0.39 and a P value of 0.058. The SCR employing the modified regularizing covariance matrix against Gleason score found a correlation of R=0.52 and a P value of 0.007. A linear fit of the SCR from filtering out 3 and 4 eigenvectors from the covariance matrix against Gleason score found correlations of R=0.50 and 0.44, respectively, and P values of 0.011 and 0.027, respectively.ConclusionsZ-score and SCR using filtered and regularized covariance matrices derived from spatially registered multi-parametric MRI correlates with Gleason score with highly significant P values.

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Unbiased data mining identifies cell cycle transcripts that predict non-indolent Gleason score 7 prostate cancer.

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Unbiased data mining identifies cell cycle transcripts that predict non-indolent Gleason score 7 prostate cancer.

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