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Molecular differences in transition zone and peripheral zone prostate tumors.

ABSTRACT: Prostate tumors arise primarily in the peripheral zone (PZ) of the prostate, but 20-30% arise in the transition zone (TZ). Zone of origin may have prognostic value or reflect distinct molecular subtypes; however, it can be difficult to determine in practice. Using whole-genome gene expression, we built a signature of zone using normal tissue from five individuals and found that it successfully classified nine tumors of known zone. Hypothesizing that this signature captures tumor zone of origin, we assessed its relationship with clinical factors among 369 tumors of unknown zone from radical prostatectomies (RPs) and found that tumors that molecularly resembled TZ tumors showed lower mortality (P = 0.09) that was explained by lower Gleason scores (P = 0.009). We further applied the signature to an earlier study of 88 RP and 333 transurethral resection of the prostate (TURP) tumor samples, also of unknown zone, with gene expression on ~6000 genes. We had observed previously substantial expression differences between RP and TURP specimens, and hypothesized that this might be because RPs capture primarily PZ tumors, whereas TURPs capture more TZ tumors. Our signature distinguished these two groups, with an area under the receiver operating characteristic curve of 87% (P < 0.0001). Our findings that zonal differences in normal tissue persist in tumor tissue and that these differences are associated with Gleason score and sample type suggest that subtypes potentially resulting from different etiologic pathways might arise in these zones. Zone of origin may be important to consider in prostate tumor biomarker research.

SUBMITTER: Sinnott JA

PROVIDER: S-EPMC4572920 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate.MethodsPatients with prostate cancer were included in the study if they had a tumor with Gleason grade 3 in the PZ, the TZ, or both (n=16). Normal prostate tissue was collected from men undergoing cystoprostatectomy (n=20). The expression of 667 unique miRNAs was investigated using TaqMan low density arrays for miRNAs. Student's t-test was used in order to identify differentially expressed miRNAs, followed by hierarchical clustering and principal component analysis (PCA) to study the separation of the tissues. The ADtree algorithm was used to identify markers for classification of tissues and a cross-validation procedure was used to test the generality of the identified miRNA-based classifiers.ResultsThe t-tests revealed that the major differences in miRNA expression are found between normal and malignant tissues. Hierarchical clustering and PCA based on differentially expressed miRNAs between normal and malignant tissues showed perfect separation between samples, while the corresponding analyses based on differentially expressed miRNAs between the two zones showed several misplaced samples. A classification and cross-validation procedure confirmed these results and several potential miRNA markers were identified.ConclusionsThe results of this study indicate that the major differences in the transcription program are those arising during tumor development, rather than during normal tissue development. In addition, tumors arising in the TZ have more unique differentially expressed miRNAs compared to the PZ. The results also indicate that separate miRNA expression signatures for diagnosis might be needed for tumors arising in the different zones. MicroRNA signatures that are specific for PZ and TZ tumors could also lead to more accurate prognoses, since tumors arising in the PZ tend to be more aggressive than tumors arising in the TZ.

Project description:The peripheral zone (PZ) and transition zone (TZ) represent about 70% of the human prostate gland with each zone having differential ability to develop prostate cancer. Androgens and their receptor are the primary driving cause of prostate cancer growth and eventually castration-resistant prostate cancer (CRPC). De novo steroidogenesis has been identified as a key mechanism that develops during CRPC. Currently, there is very limited information available on human prostate tissue steroidogenesis. The purpose of the present study was to investigate steroid metabolism in human prostate cancer tissues with comparison between PZ and TZ. Human prostate cancer tumors were procured from the patients who underwent radical prostatectomy without any neoadjuvant therapy. Human prostate homogenates were used to quantify steroid levels intrinsically present in the tissues as well as formed after incubation with 2 µg/mL of 17-hydroxypregnenolone (17-OH-pregnenolone) or progesterone. A Waters Acquity ultraperformance liquid chromatography coupled to a Quattro Premier XE tandem quadrupole mass spectrometer using a C18 column was used to measure thirteen steroids from the classical and backdoor steroidogenesis pathways. The intrinsic prostate tissue steroid levels were similar between PZ and TZ with dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), pregnenolone and 17-OH-pregnenolone levels higher than the other steroids measured. Interestingly, 5-pregnan-3,20-dione, 5-pregnan-3-ol-20-one, and 5-pregnan-17-ol-3,20-dione formation was significantly higher in both the zones of prostate tissues, whereas, androstenedione, testosterone, DHT, and progesterone levels were significantly lower after 60 min incubation compared to the 0 min control incubations. The incubations with progesterone had a similar outcome with 5-pregnan-3,20-dione and 5-pregnan-3-ol-20-one levels were elevated and the levels of DHT were lower in both PZ and TZ tissues. The net changes in steroid formation after the incubation were more observable with 17-OH-pregnenolone than with progesterone. In our knowledge, this is the first report of comprehensive analyses of intrinsic prostate tissue steroids and precursor-driven steroid metabolism using a sensitive liquid chromatography-mass spectrometry assay. In summary, the PZ and TZ of human prostate exhibited similar steroidogenic ability with distinction in the manner each zone utilizes the steroid precursors to divert the activity towards backdoor pathway through a complex matrix of steroidogenic mechanisms.

Project description:OBJECTIVE:This study aims for targeted biopsy validation of magnetic resonance fingerprinting (MRF) and diffusion mapping for characterizing peripheral zone (PZ) prostate cancer and noncancers. MATERIALS AND METHODS:One hundred four PZ lesions in 85 patients who underwent magnetic resonance imaging were retrospectively analyzed with apparent diffusion coefficient (ADC) mapping, MRF, and targeted biopsy (cognitive or in-gantry). A radiologist blinded to pathology drew regions of interest on targeted lesions and visually normal peripheral zone on MRF and ADC maps. Mean T1, T2, and ADC were analyzed using linear mixed models. Generalized estimating equations logistic regression analyses were used to evaluate T1 and T2 relaxometry combined with ADC in differentiating pathologic groups. RESULTS:Targeted biopsy revealed 63 cancers (low-grade cancer/Gleason score 6 = 10, clinically significant cancer/Gleason score ?7 = 53), 15 prostatitis, and 26 negative biopsies. Prostate cancer T1, T2, and ADC (mean ± SD, 1660 ± 270 milliseconds, 56 ± 20 milliseconds, 0.70 × 10 ± 0.24 × 10 mm/s) were significantly lower than prostatitis (mean ± SD, 1730 ± 350 milliseconds, 77 ± 36 milliseconds, 1.00 × 10 ± 0.30 × 10 mm/s) and negative biopsies (mean ± SD, 1810 ± 250 milliseconds, 71 ± 37 milliseconds, 1.00 × 10 ± 0.33 × 10 mm/s). For cancer versus prostatitis, ADC was sensitive and T2 specific with comparable area under curve (AUC; (AUCT2 = 0.71, AUCADC = 0.79, difference between AUCs not significant P = 0.37). T1 + ADC (AUCT1 + ADC = 0.83) provided the best separation between cancer and negative biopsies. Low-grade cancer T2 and ADC (mean ± SD, 75 ± 29 milliseconds, 0.96 × 10 ± 0.34 × 10 mm/s) were significantly higher than clinically significant cancers (mean ± SD, 52 ± 16 milliseconds, 0.65 ± 0.18 × 10 mm/s), and T2 + ADC (AUCT2 + ADC = 0.91) provided the best separation. CONCLUSIONS:T1 and T2 relaxometry combined with ADC mapping may be useful for quantitative characterization of prostate cancer grades and differentiating cancer from noncancers for PZ lesions seen on T2-weighted images.

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Molecular differences in transition zone and peripheral zone prostate tumors.

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