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Molecular profiling of radical prostatectomy tissue from patients with no sign of progression identifies ERG as the strongest independent predictor of recurrence.

ABSTRACT: BACKGROUND:As a major cause of morbidity and mortality among men, prostate cancer is a heterogenous disease, with a vast heterogeneity in the biology of the disease and in clinical outcome. While it often runs an indolent course, local progression or metastasis may eventually develop, even among patients considered "low risk" at diagnosis. Therefore, biomarkers that can discriminate aggressive from indolent disease at an early stage would greatly benefit patients. We hypothesized that tissue specimens from early stage prostate cancers may harbor predictive signatures for disease progression. METHODS:We used a cohort of radical prostatectomy patients with longitudinal follow-up, who had tumors with low grade and stage that revealed no signs of future disease progression at surgery. During the follow-up period, some patients either remained indolent (non-BCR) or progressed to biochemical recurrence (BCR). Total RNA was extracted from tumor, and adjacent normal epithelium of formalin-fixed-paraffin-embedded (FFPE) specimens. Differential gene expression in tumors, and in tumor versus normal tissues between BCR and non-BCR patients were analyzed by NanoString using a customized CodeSet of 151 probes. RESULTS:After controlling for false discovery rates, we identified a panel of eight genes (ERG, GGT1, HDAC1, KLK2, MYO6, PLA2G7, BICD1 and CACNAID) that distinguished BCR from non-BCR patients. We found a clear association of ERG expression with non-BCR, which was further corroborated by quantitative RT-PCR and immunohistochemistry assays. CONCLUSIONS:Our results identified ERG as the strongest predictor for BCR and showed that potential prognostic prostate cancer biomarkers can be identified from FFPE tumor specimens.

SUBMITTER: Yan W

PROVIDER: S-EPMC6849651 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Molecular profiling of radical prostatectomy tissue from patients with no sign of progression identifies <i>ERG</i> as the strongest independent predictor of recurrence.

Yan Wusheng W Jamal Muhammad M Tan Shyh-Han SH Song Yingjie Y Young Denise D Chen Yongmei Y Katta Shilpa S Ying Kai K Ravindranath Lakshmi L Woodle Tarah T Kohaar Indu I Cullen Jennifer J Kagan Jacob J Srivastava Sudhir S Dobi Albert A McLeod David G DG Rosner Inger L IL Sesterhenn Isabell A IA Srinivasan Alagarsamy A Srivastava Shiv S Petrovics Gyorgy G

Oncotarget 20191105 60

<h4>Background</h4>As a major cause of morbidity and mortality among men, prostate cancer is a heterogenous disease, with a vast heterogeneity in the biology of the disease and in clinical outcome. While it often runs an indolent course, local progression or metastasis may eventually develop, even among patients considered "low risk" at diagnosis. Therefore, biomarkers that can discriminate aggressive from indolent disease at an early stage would greatly benefit patients. We hypothesized that ti ...[more]

PMID: 31741711

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Project description:We have previously demonstrated a significant correlative relationship between PTEN deletion and ERG rearrangement, both in the development of clinically localized prostate cancers and metastases. Herein, we evaluate the cooperative role of ERG and PTEN in oncological outcomes after radical prostatectomy for clinically localized prostate cancer. We evaluated ERG and PTEN status using three previously described cohorts. The first cohort included 235 clinically localized prostate cancer cases represented on tissue microarrays (TMA), evaluated using previously validated FISH assays for ERG and PTEN. The second cohort included 167 cases of clinically localized prostate cancer on TMAs evaluated for PTEN by FISH, and for PTEN and ERG by dual IHC. The third cohort comprised 59 clinically localized prostate cancer cases assessed by array comparative genomic hybridization (aCGH). Kaplan-Meir plots and long rank tests were used to assess the association of ERG and PTEN status with biochemical recurrence after radical prostatectomy for clinically localized prostate cancer. Of the 317 cases eligible for analyses with evaluable ERG and PTEN status, 88 (27.8%) patients developed biochemical recurrence over a median follow-up of 5.7 years. Overall, 45% (142/317) of cases demonstrated ERG rearrangement and 20% (62/317) of cases demonstrated PTEN loss. Hemizygous and homozygous deletion of PTEN was seen in 10% (18/175) and 3% (5/175) of ERG-negative cases, respectively. In contrast, hemizygous and homozygous deletion of PTEN was seen in 11% (15/142) and 17% (24/123) of ERG-positive cases, respectively. PTEN loss (heterozygous or homozygous) was significantly associated with shorter time to biochemical recurrence compared to no PTEN loss (p < 0.001). However, ERG rearrangement versus no rearrangement was not associated with time to PSA recurrence (p = 0.15). Patients who exhibited ERG rearrangement and loss of PTEN had no significant difference in time to recurrence compared to patients with wild-type ERG and loss of PTEN (p = 0.30). Our findings confirm a mutual cooperative role of ERG and PTEN in the pathogenesis of prostate cancer, particularly for homozygous PTEN deletion. ERG did not stratify outcome either alone or in combination with PTEN in this cohort.

Project description:BackgroundPreoperative PSA, ISUP grade group (GG), prostate examination and multiparametric MRI (mpMRI) form the basis of prostate cancer staging. Unlike other solid organ tumours, tumour volume (TV) is not routinely used aside from crude estimates such as maximum cancer core length. The aim of this study is to assess the role of TV as a marker for oncological outcomes in high-risk non-metastatic prostate cancer.MethodsA prospectively maintained database of patients undergoing minimally invasive (laparoscopic or robot-assisted laparoscopic) radical prostatectomy at a UK centre between 2007 and 2019 were analysed. A total of 251 patients with NCCN high or very high-risk prostate cancer were identified. Primary outcome measure was time to biochemical recurrence (BCR) and the secondary outcome was time to treatment failure (TTF). TV was measured on the pathological specimen using the stacking method. Multivariable cox regression analysis was used to identify factors predicting BCR and TFF. TV as a predictor of BCR and TFF was further analysed through time-dependent receiver operating characteristic (ROC) curves. Kaplan-Meier survival estimates were used to evaluate TV cut-off scores.ResultsMedian follow up was 4.50 years. Four factors were associated with BCR and TFF on multivariable analysis (TV, pathological GG, pathological T stage, positive margin >3 mm). Area under the Curve (AUC) for TV as a predictor of BCR and TTF at 5 years was 0.71 and 0.75, respectively. Including all 4 variables in the model increased AUC to 0.84 and 0.85 for BCR and TFF. A 2.50 cm TV cut off demonstrated a significance difference in time to BCR, p < 0.001.ConclusionsPathological tumour volume is an independent predictor of oncological outcomes in high risk prostate cancer but does not add significant prognostic value when combined with established variables. However, the option of accurate TV measurement on mpMRI raises the possibility of using TV as useful marker for preoperative risk stratification.

Project description:The objective of this study was to utilize a microarray platform to determine the microRNA (miRNA) expression profile in prostate cancer tissue from patients who underwent radical prostatectomy and were followed for an average of 47 months. The GeneChip® miRNA Array (Affymetrix) contains more than 46,000 probes, and more than 1,100 mature human miRNAs and transcripts. An expression level higher or lower than 1.1 with a p<0.05 were considered to be differentially expressed. When tumors with a GS<7 were compared with those with a GS≥7, five miRNAs were down-regulated and nine were up-regulated. In comparing tumors from patients with PSA <10 ng/mL vs. those with PSA ≥10 ng/mL, 21 miRNAs were down-regulated and 29 were overexpressed. There was decreased expression of 21 miRNAs and increased expression of 22 miRNAs when pT2 and pT3 tumors were compared. The comparison of the expression profiles of men with vs. without recurrent disease (PSA>0.2 ng/mL) revealed that 14 miRNAs were down-regulated and 17 were up-regulated. Considering the three prognostic factors and biochemical recurrence, miR-335 was overexpressed in pT3 tumors in patients with PSA>10 ng/mL, miR-1202 was overexpressed in recurrent tumors in which PSA >10 ng/mL, and miR-885 and miR-1226 were overexpressed in recurrent pT3 tumors. Six miRNAs (miR- 361, 378, 548, 574, 652 and 892) had decreased expression in pT3 tumors in patients with PSA >10 ng/mL. miR-16 was down-regulated in recurrent pT3 tumors. miR-92 and miR-450 exhibited decreased expression in recurrent tumors in patients with PSA > 10 ng/mL. miR-28 was down-regulated in pT3 adenocarcinomas with a GS ≥ 7. The differentially expressed miRNAs in recurrent tumors were validated using qRT-PCR in 74 additional specimens. miR-21 was overexpressed in recurrent tumors, and in the Cox model, expression levels higher than 0.64 were indicative of biochemical recurrence with a risk of 2.4. These results, which were based on clinical specimens from patients treated in a standardized way and followed for an average of 47 months, provide an initial understanding of the role of miRNAs in prostatecancer progression; the foremost representative is miR-21, which has been implicated in the progression of various human cancers.

Dataset Information

Molecular profiling of radical prostatectomy tissue from patients with no sign of progression identifies ERG as the strongest independent predictor of recurrence.

Publications

Molecular profiling of radical prostatectomy tissue from patients with no sign of progression identifies <i>ERG</i> as the strongest independent predictor of recurrence.

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