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Gene-expression analysis of gleason grade 3 tumor glands embedded in low- and high-risk prostate cancer.

ABSTRACT: The Gleason score (GS) of prostate cancer on diagnostic biopsies is an important parameter for therapeutic decision-making. Biopsy GS under-estimates the actual GS at radical prostatectomy in a significant number of patients due to samplingartifact. The aim of this study was to identify markers that are differentially expressed in Gleason grade 3 (GG3) tumor glands embedded in GS 4 + 3 = 7 and GS 3 + 3 = 6 prostate cancer using laser capture microdissection and RNA sequencing.GG3 tumor glands embedded in nine GS 3 + 3 = 6 and nine GS 4 + 3 = 7 prostate cancers were isolated by laser capture microdissection of frozen radical prostatectomy specimens. After RNA amplification and RNA sequencing, differentially expressed genes in both GG3 components were identified by a 2log fold change > 1.0 and p-value < 0.05. We applied immunohistochemistry on a tissue micro-array representing 481 radical prostatectomy samples for further validation on protein level.A total of 501 genes were up-regulated and 421 down-regulated in GG3 glands embedded in GS 4 + 3 = 7 as compared to GS 3 + 3 = 6 prostate cancer. We selected HELLS, ZIC2 and ZIC5 genes for further validation. ZIC5 mRNA was up-regulated 17 fold (p = 8.4E-07), ZIC2 8 fold (p = 1.3E-05) and HELLS 2 fold (p = 0.006) in GG3 glands derived from GS 4 + 3 = 7. HELLS expression of ? 1% occurred in 10% GS < 7, 17% GS 7 and 43% GS >7 prostate cancer (p < 0.001). Using a cut-off of ? 1%, protein expression of ZIC5 was present in 28% GS < 7, 43% GS 7 and 57% GS > 7 cancer (p < 0.001). ZIC2 was neither associated with GS nor outcome in our validation set. HELLS was independently predictive for biochemical-recurrence after radical prostatectomy (HR 2.3; CI 1.5-3.6; p < 0.01).In conclusion, HELLS and ZIC5 might be promising candidate markers for selection of biopsy GS 6 prostate cancer being at risk for up-grading at prostatectomy.

SUBMITTER: Hoogland AM

PROVIDER: S-EPMC5122354 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Gene-expression analysis of gleason grade 3 tumor glands embedded in low- and high-risk prostate cancer.

Hoogland A Marije AM Böttcher René R Verhoef Esther E Jenster Guido G van Leenders Geert J L H GJ

Oncotarget 20160601 25

The Gleason score (GS) of prostate cancer on diagnostic biopsies is an important parameter for therapeutic decision-making. Biopsy GS under-estimates the actual GS at radical prostatectomy in a significant number of patients due to samplingartifact. The aim of this study was to identify markers that are differentially expressed in Gleason grade 3 (GG3) tumor glands embedded in GS 4 + 3 = 7 and GS 3 + 3 = 6 prostate cancer using laser capture microdissection and RNA sequencing.GG3 tumor glands em ...[more]

PMID: 27191985

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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.

Dataset Information

Gene-expression analysis of gleason grade 3 tumor glands embedded in low- and high-risk prostate cancer.

Publications

Gene-expression analysis of gleason grade 3 tumor glands embedded in low- and high-risk prostate cancer.

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