The Association between Cyclin Dependent Kinase 2 Associated Protein 1 (CDK2AP1) and Molecular Subtypes of Lethal Prostate Cancer.

Prostate cancer (PCa) is one of the most commonly diagnosed types of malignancy and is the second leading cause of cancer-related death in men in developed countries. Cyclin dependent kinase 2 associate protein 1(CDK2AP1) is an epigenetic and cell cycle regulator gene which has been downregulated in several malignancies, but its involvement in PCa has not yet been investigated in a clinical setting. We assessed the prognostic value of CDK2AP1 expression in a cohort of men diagnosed with PCa (n = 275) treated non-surgically by transurethral resection of the prostate (TURP) and studied the relationship between CDK2AP1 expression to various PCa molecular subtypes (ERG, PTEN, p53 and AR) and evaluated the association with clinical outcome. Further, we used bioinformatic tools to analyze the available TCGA PRAD transcriptomic data to explore the underlying mechanism. Our data confirmed increased expression of CDK2AP1 with higher Gleason Grade Group (GG) and metastatic PCa (p <0.0001). High CDK2AP1 expression was associated with worse overall survival (OS) (HR: 1.62, CI: 1.19−2.21, p = 0.002) and cause-specific survival (CSS) (HR: 2.012, CI 1.29−3.13, p = 0.002) using univariate analysis. When compared to each sub-molecular type. High CDK2AP1/PTEN-loss, abnormal AR or p53 expression showed even worse association to poorer OS and CCS and remained significant when adjusted for GG. Our data indicates that CDK2AP1 directly binds to p53 using the Co-Immunoprecipitation (Co-IP) technique, which was validated using molecular docking tools. This suggests that these two proteins have a significant association through several binding features and correlates with our observed clinical data. In conclusion, our results indicated that the CDK2AP1 overexpression is associate with worse OS and CSS when combined with certain PCa molecular subtypes; interaction between p53 stands out as the most prominent candidate which directly interacts with CDK2AP1.

Decipher identifies men with otherwise clinically favorable-intermediate risk disease who may not be good candidates for active surveillance.

BACKGROUND: We aimed to validate Decipher to predict adverse pathology (AP) at radical prostatectomy (RP) in men with National Comprehensive Cancer Network (NCCN) favorable-intermediate risk (F-IR) prostate cancer (PCa), and to better select F-IR candidates for active surveillance (AS). METHODS: In all, 647 patients diagnosed with NCCN very low/low risk (VL/LR) or F-IR prostate cancer were identified from a multi-institutional PCa biopsy database; all underwent RP with complete postoperative clinicopathological information and Decipher genomic risk scores. The performance of all risk assessment tools was evaluated using logistic regression model for the endpoint of AP, defined as grade group 3-5, pT3b or higher, or lymph node invasion. RESULTS: The median age was 61 years (interquartile range 56-66) for 220 patients with NCCN F-IR disease, 53% classified as low-risk by Cancer of the Prostate Risk Assessment (CAPRA 0-2) and 47% as intermediate-risk (CAPRA 3-5). Decipher classified 79%, 13% and 8% of men as low-, intermediate- and high-risk with 13%, 10%, and 41% rate of AP, respectively. Decipher was an independent predictor of AP with an odds ratio of 1.34 per 0.1 unit increased (p value = 0.002) and remained significant when adjusting by CAPRA. Notably, F-IR with Decipher low or intermediate score did not associate with significantly higher odds of AP compared to VL/LR. CONCLUSIONS: NCCN risk groups, including F-IR, are highly heterogeneous and should be replaced with multivariable risk-stratification. In particular, incorporating Decipher may be useful for safely expanding the use of AS in this patient population.

Validation of the Decipher Test for predicting adverse pathology in candidates for prostate cancer active surveillance.

ABSTACT: BACKGROUND: Many men diagnosed with prostate cancer are active surveillance (AS) candidates. However, AS may be associated with increased risk of disease progression and metastasis due to delayed therapy. Genomic classifiers, e.g., Decipher, may allow better risk-stratify newly diagnosed prostate cancers for AS. METHODS: Decipher was initially assessed in a prospective cohort of prostatectomies to explore the correlation with clinically meaningful biologic characteristics and then assessed in diagnostic biopsies from a retrospective multicenter cohort of 266 men with National Comprehensive Cancer Network (NCCN) very low/low and favorable-intermediate risk prostate cancer. Decipher and Cancer of the Prostate Risk Assessment (CAPRA) were compared as predictors of adverse pathology (AP) for which there is universal agreement that patients with long life-expectancy are not suitable candidates for AS (primary pattern 4 or 5, advanced local stage [pT3b or greater] or lymph node involvement). RESULTS: Decipher from prostatectomies was significantly associated with adverse pathologic features (p-values < 0.001). Decipher from the 266 diagnostic biopsies (64.7% NCCN-very-low/low and 35.3% favorable-intermediate) was an independent predictor of AP (odds ratio 1.29 per 10% increase, 95% confidence interval [CI] 1.03-1.61, p-value 0.025) when adjusting for CAPRA. CAPRA area under curve (AUC) was 0.57, (95% CI 0.47-0.68). Adding Decipher to CAPRA increased the AUC to 0.65 (95% CI 0.58-0.70). NPV, which determines the degree of confidence in the absence of AP for patients, was 91% (95% CI 87-94%) and 96% (95% CI 90-99%) for Decipher thresholds of 0.45 and 0.2, respectively. Using a threshold of 0.2, Decipher was a significant predictor of AP when adjusting for CAPRA (p-value 0.016). CONCLUSION: Decipher can be applied to prostate biopsies from NCCN-very-low/low and favorable-intermediate risk patients to predict absence of adverse pathologic features. These patients are predicted to be good candidates for active surveillance.

The prognostic significance of combined ERG and androgen receptor expression in patients with prostate cancer managed by androgen deprivation therapy.

ERG and androgen receptor (AR) are known to function cooperatively in prostate cancer (PCa) progression. However, the prognostic value of combined ERG and AR expression and potential pathways are not well characterized. We assessed ERG and AR protein expression by immunohistochemistry in a cohort of 312 men with PCa diagnosed by transurethral resection of the prostate (TURP). Patients were divided into those with no prior hormonal treatment (designated as PCa/AdvPCa) vs. those with castrate-resistant PCa (CRPC) undergoing channel TURP to relieve obstructive symptoms. The expression status was correlated with various clinical-pathological parameters. The Swedish watchful-waiting cohort was used for validation and characterization of potential gene signatures associated with ERG and AR.   Patients with combined ERG-positive/AR high expression profile demonstrated higher rates of PCa-specific mortality (PCSM) compared with patients with ERG-negative/AR low in patients with no prior treatment (n = 90, P = 0.032), but this was attenuated in the overall cohort which included the CRPC subgroup (n = 125, P = 0.096). The prognostic significance to PCSM was validated in the Swedish watchful waiting cohort in univariate (HR: 3.3; 95% CI: 1.9-5.6, P = 4.25E-5) and multivariate analysis (HR: 2; 95% CI: 0.97-4.1, P = 0.057), which included Gleason score. ERG/AR overexpression status characterized 152 genes signatures including WNT, PI3K/AKT and chemokine signaling pathways known to be deregulated in PCa. In conclusion, combined ERG/AR overexpression signifies a class of patients at highest-risk of PCSM with specific key genetic alteration likely responsible for disease progression. The prognostic value of combined ERG/AR overexpression and its associated genes should be further investigated as potential prognostic and therapeutic targets in prostate cancer progression.

Detection of ERG gene rearrangements and PTEN deletions in unsuspected prostate cancer of the transition zone.

To assess the incidence of ERG rearrangements and PTEN deletions in a group of prognostically favorable PCA tumors of the transition zone (TZ). We interrogated 54 unsuspected PCA tumors using fluorescence in-situ hybridization for ERG rearrangements and PTEN deletions. ERG rearrangements were detected in 6/47 (12.7%) cases with 4/6 (66%) occurring by deletion. PTEN deletions were detected in 9/47 (19.1%) cases with only 3/47 (6.4%) having both PTEN losses and ERG rearrangements (p = 0.07). Only ERG rearrangements were associated with higher tumor volume > 5% (p = 0.04); PTEN deletions showed similar trends (p = 0.06). None of the markers showed association with Gleason score. In conclusion, although TZ and peripheral zone tumors share similar molecular etiologies, they exhibit differences in the rates of ERG and PTEN aberrations. The differences of ERG and /or PTEN genetic aberrations in TZ tumors may point toward a subset of tumors with adverse behavior. Additional studies implementing ERG and PTEN tissue-based FISH assays in tumors of the TZ are warranted to substantiate the potential clinical value of these biomarkers in the management of men with incidental PCA.