Stratification of aggressive prostate cancer from indolent disease—Prospective controlled trial utilizing expression of 11 genes in apparently benign tissue

Alinezhad, Saeid; Väänänen, Riina‐Minna; Tallgrén, Terhi; Perez, Ileana Montoya; Jambor, Ivan; Aronen, Hannu J.; Kähkönen, Esa; Ettala, Otto; Syvänen, Kari; Nees, Matthias; Kallajoki, Markku; Taimen, Pekka; Boström, Peter J.; Pettersson, Kim

doi:10.1016/j.urolonc.2015.12.014

Cited by 10 publications

(14 citation statements)

References 27 publications

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“…Cox regression model showing the predictive power of T2E fusion status + MMP-2 altered expression on subsequent PC diagnosis PCA3 expression was not discriminant for PC diagnosis in patients withASAP. In addition to our present results, the expression of PCA3 alone has been reported to show no difference between benign or benign hyperplastic prostate samples and tissue samples with low or high grade intraepithelial neoplasia; however, the increased expression of PCA3 has only been detected in peripheral blood samples and tissue specimens with PC 60,63,64. The lack of a significant increase in PCA3 expression is probably because the PC phenotype has not yet emerged from this suspicious focus or there is an unsampled relatively small area, still compatible with the PC phenotype, adjacent to ASAP site.…”

supporting

confidence: 69%

“…Although these findings were important in terms of confirming the compatibility of the study, we revealed that KLK3 did not predict PC risk at the RNA level in ASAP‐diagnosed patients. Similarly, a recent study demonstrated that KLK3 expression at the RNA level was reported as lacking any diagnostic power in benign prostatic tissue samples of men with a clinical suspicion of PC . Based on existing results, although KLK3 expression was not a potential for PC risk assessment in diagnostically challenging tissue samples, it has been shown to be a useful marker in the peripheral blood mononuclear cell fraction for predicting prognosis in CRPC patients receiving systemic therapy .…”

Section: Discussionmentioning

confidence: 99%

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RNA‐based markers in biopsy cores with atypical small acinar proliferation: Predictive effect of T2E fusion positivity and MMP‐2 upregulation for a subsequent prostate cancer diagnosis

et al. 2018

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Background Atypical small acinar proliferation (ASAP) is a precursor lesion of prostate cancer (PC), and PC develops from this suspicious focus or an unsampled malignant gland nearby. However, PC‐related molecular alterations that could guide the timing of repeat biopsies and help monitor PC risk in ASAP‐diagnosed patients have not been investigated. The purpose of this study was to first investigate the expression of seven different PC‐related RNAs that included serine 2 (TMPRSS2): erythroblastosis virus E26 oncogene homolog (ERG) gene (TMPRSS2‐ERG, T2E) fusion, alpha‐methylacyl‐CoA racemase (AMACR), kallikrein related peptidase 3 (KLK3), androgen receptor (AR), prostate cancer specific antigen 3 (PCA3), and matrix metalloproteinases (MMP)‐2 and 9. Methods PC‐related RNAs were evaluated using a real‐time quantitative reverse transcription polymerase chain reaction (RT‐qPCR) system in pathologically ASAP‐diagnosed prostate biopsy cores from 55 patients presenting with a normal digital rectal examination and a PSA level of 4‐10 ng/mL. Results We detected that positive T2E fusion status (P = 0.013) and the expression of AMACR (P = 0.016), AR (P = 0.016) and MMP‐2 (P = 0.013) were independently and significantly associated with PC risk in ASAP patients. There were also several statistically significant correlations between expression levels. Additionally, we demonstrated that T2E fusion positive ASAP patients with higher MMP‐2 expression were more likely to be diagnosed with PC at a subsequent biopsy during the follow‐up period (P = 0.003). Conclusions Although, more clinical validations are needed for the stratification of PC risk in ASAP‐diagnosed biopsy cores, our current results indicate that the coexistence of T2E fusion positivity with MMP‐2 upregulation may help clinicians adjust their biopsy timetable and/or assessment of PC risk in ASAP‐diagnosed patients with a PSA level of 4‐10 ng/mL.

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supporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

RNA‐based markers in biopsy cores with atypical small acinar proliferation: Predictive effect of T2E fusion positivity and MMP‐2 upregulation for a subsequent prostate cancer diagnosis

et al. 2018

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“…It may also be that FFPE tissues do not preserve differential expression of all RNAs. Of note, previous analyses of PCA3 expression in PBx tissues have reported inconsistencies, with both upregulation in cancer and no difference between malignant and normal prostate [21, 22] [23]. …”

Section: Discussionmentioning

confidence: 99%

Evaluation of a short RNA within Prostate Cancer Gene 3 in the predictive role for future cancer using non-malignant prostate biopsies

et al. 2017

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BackgroundProstate Cancer 3 (PCA3) is a long non-coding RNA (ncRNA) upregulated in prostate cancer (PCa). We recently identified a short ncRNA expressed from intron 1 of PCA3. Here we test the ability of this ncRNA to predict the presence of cancer in men with a biopsy without PCa.MethodsWe selected men whose initial biopsy did not identify PCa and selected matched cohorts whose subsequent biopsies revealed PCa or benign tissue. We extracted RNA from the initial biopsy and measured PCA3-shRNA2, PCA3 and PSA (qRT-PCR).ResultsWe identified 116 men with and 94 men without an eventual diagnosis of PCa in 2–5 biopsies (mean 26 months), collected from 2002–2008. The cohorts were similar for age, PSA and surveillance period. We detected PSA and PCA3-shRNA2 RNA in all samples, and PCA3 RNA in 90% of biopsies. The expression of PCA3 and PCA3-shRNA2 were correlated (Pearson’s r = 0.37, p<0.01). There was upregulation of PCA3 (2.1-fold, t-test p = 0.02) and PCA3-shRNA2 (1.5-fold) in men with PCa on subsequent biopsy, although this was not significant for the latter RNA (p = 0.2). PCA3 was associated with the future detection of PCa (C-index 0.61, p = 0.01). This was not the case for PCA3-shRNA2 (C-index 0.55, p = 0.2).ConclusionsPCA3 and PCA3-shRNA2 expression are detectable in historic biopsies and their expression is correlated suggesting co-expression. PCA3 expression was upregulated in men with PCa diagnosed at a future date, the same did not hold for PCA3-shRNA2. Futures studies should explore expression in urine and look at a time course between biopsy and PCa detection.

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“…Thus, development and validation of more cost‐effective prostate MRI protocol for improved PCa risk stratification in men with elevated PSA is needed . The prospective single‐institutional IMPROD clinical trial (NCT01864135, IMPROD = Improved Prostate Cancer Diagnosis – Combination of Magnetic Resonance Imaging and Biomarkers, http://mrc.utu.fi/mri/improd) was initiated to evaluate performance of a unique MRI protocol, IMPROD biparametric MRI (bpMRI) protocol, and selected biomarkers in men with a clinical suspicion of PCa based on elevated PSA and/or abnormal DRE. The IMPROD bpMRI protocol uses surface array coils (no endorectal coil) and no intravenous contrast agent.…”

mentioning

confidence: 99%

“…In previous studies, expressions of 11 genes (ie, ACSM1, AMACR, CACNA1D, DLX1, PCA3, PLA2G7, RHOU, SPINK1, SPON2, TMPRSS2‐ERG, and TDRD1) in histologically benign prostate tissue from PCa patients were investigated to determine their diagnostic performance . Furthermore, it has been shown that the expression of TDRD1 and TMPRSS2‐ERG mRNA is significantly different ( P < 0.05) in men with PCa compared with men without PCa . However, the added value of these biomarkers combined with IMPROD bpMRI and other clinical variables has not been explored.…”

mentioning

confidence: 99%

Prostate Cancer Risk Stratification in Men With a Clinical Suspicion of Prostate Cancer Using a Unique Biparametric MRI and Expression of 11 Genes in Apparently Benign Tissue: Evaluation Using Machine‐Learning Techniques

Perez

Jambor

Pahikkala

et al. 2019

Magnetic Resonance Imaging

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Background: Accurate risk stratification of men with a clinical suspicion of prostate cancer (cSPCa) remains challenging despite the increasing use of MRI. Purpose: To evaluate the diagnostic accuracy of a unique biparametric MRI protocol (IMPROD bpMRI) combined with clinical and molecular markers in men with cSPCa. Study Type: Prospective single-institutional clinical trial (NCT01864135). Subjects: Eighty men with cSPCa. Field Strength/Sequence: 3T, surface array coils. Two T 2 -weighted and three diffusion-weighted imaging (DWI) acquisitions: 1) b-values 0, 100, 200, 300, 500 s/mm 2 ; 2) b-values 0,1500 s/mm 2 ; 3) b-values 0, 2000 s/mm 2 . Assessment: IMPROD bpMRI examinations were qualitatively (IMPROD bpMRI Likert score) and quantitatively (DWI-based Gleason grade score) prospectively reported. Men with IMPROD bpMRI Likert 3-5 had two targeted biopsies followed by 12-core systematic biopsies (SB); those with IMPROD bpMRI Likert 1-2 had only SB. Additionally, 2-core from normalappearing prostate areas were obtained for the mRNA expression of ACSM1, AMACR, CACNA1D, DLX1, PCA3, PLA2G7, RHOU, SPINK1, SPON2, TMPRSS2-ERG, and TDRD1 measured by quantitative reverse-transcription polymerase chain reaction. Statistical Tests: Univariate and multivariate analysis using regularized least-squares, feature selection and tournament leave-pair-out cross-validation (TLPOCV), as well as 10 random splits of the data in training-testing sets, were used to evaluate the mRNA, clinical and IMPROD bpMRI parameters in detecting clinically significant prostate cancer (SPCa) defined as Gleason score ≥ 3 + 4. The evaluation metric was the area under the curve (AUC). Results: IMPROD bpMRI Likert demonstrated the highest TLPOCV AUC of 0.92. The tested clinical variables had AUC 0.56-0.73, while the mRNA and additional IMPROD bpMRI parameters had AUC 0.50-0.67 and 0.65-0.89 respectively.View this article online at wileyonlinelibrary.com.

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Stratification of aggressive prostate cancer from indolent disease—Prospective controlled trial utilizing expression of 11 genes in apparently benign tissue

Cited by 10 publications

References 27 publications

RNA‐based markers in biopsy cores with atypical small acinar proliferation: Predictive effect of T2E fusion positivity and MMP‐2 upregulation for a subsequent prostate cancer diagnosis

RNA‐based markers in biopsy cores with atypical small acinar proliferation: Predictive effect of T2E fusion positivity and MMP‐2 upregulation for a subsequent prostate cancer diagnosis

Evaluation of a short RNA within Prostate Cancer Gene 3 in the predictive role for future cancer using non-malignant prostate biopsies

Prostate Cancer Risk Stratification in Men With a Clinical Suspicion of Prostate Cancer Using a Unique Biparametric MRI and Expression of 11 Genes in Apparently Benign Tissue: Evaluation Using Machine‐Learning Techniques

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