Dataset Information

Frequent discordance between ERG gene rearrangement and ERG protein expression in a rapid autopsy cohort of patients with lethal, metastatic, castration-resistant prostate cancer.

ABSTRACT: ERG rearrangements in localized prostate cancer can be detected with high sensitivity and specificity by immunohistochemistry (IHC). However, recent data suggest that ERG IHC may be less sensitive for ERG rearrangements in castration-resistant prostate cancer (CRPC). Thus, we sought to examine ERG protein expression in a cohort of rapid autopsy patients with lethal metastatic CRPC (mCRPC).A tissue microarray (TMA) of tumor sites from these patients was evaluated for ERG, prostate-specific antigen (PSA), and androgen receptor (AR) expression by IHC and correlated with ERG rearrangement status by fluorescent in situ hybridization (FISH). IHC was scored as the product of tumor cell staining intensity (0-3) and percentage of cells positive (0-100) (overall product score range?=?0-300).All 16 (100%) ERG rearrangement negative (ERG(neg) ) patients were also negative for ERG tumor cell expression (i.e., IHC product score?=?0). Of the 10 ERG rearrangement positive (ERG(pos) ) patients, two (20%) were completely negative for ERG tumor cell expression, while eight (80%) had weak ERG expression (median IHC product score?=?5-110). Of these eight ERG(pos) patients, five (63%) had at least one tumor site without any detectable ERG expression. For a given ERG(pos) patient, ERG expression varied both between and within tumor sites; AR and PSA expression also varied between tumor sites, and there was no significant correlation between ERG and AR or PSA expression.These data reveal frequent discordance between ERG IHC and ERG FISH in ERG(pos) patients from this unique cohort of heavily treated lethal mCRPC.

SUBMITTER: Udager AM

PROVIDER: S-EPMC4156519 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Frequent discordance between ERG gene rearrangement and ERG protein expression in a rapid autopsy cohort of patients with lethal, metastatic, castration-resistant prostate cancer.

Udager Aaron M AM Shi Yang Y Tomlins Scott A SA Alva Ajjai A Siddiqui Javed J Cao Xuhong X Pienta Kenneth J KJ Jiang Hui H Chinnaiyan Arul M AM Mehra Rohit R

The Prostate 20140707 12

<h4>Background</h4>ERG rearrangements in localized prostate cancer can be detected with high sensitivity and specificity by immunohistochemistry (IHC). However, recent data suggest that ERG IHC may be less sensitive for ERG rearrangements in castration-resistant prostate cancer (CRPC). Thus, we sought to examine ERG protein expression in a cohort of rapid autopsy patients with lethal metastatic CRPC (mCRPC).<h4>Methods</h4>A tissue microarray (TMA) of tumor sites from these patients was evaluate ...[more]

PMID: 25043157

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Project description:BackgroundSystematic identification of data essential for outcome prediction in metastatic prostate cancer (mPC) would accelerate development of precision oncology.ObjectiveTo identify novel phenotypes and features associated with mPC outcome, and to identify biomarker and data requirements to be tested in future precision oncology trials.Design setting and participantsWe analyzed deep longitudinal clinical, neuroendocrine expression, and autopsy data of 33 men who died from mPC between 1995 and 2004 (PELICAN33), and related findings to mPC biomarkers reported in the literature.InterventionThirty-three men prospectively consented to participate in an integrated clinical-molecular rapid autopsy study of mPC.Outcome measurements and statistical analysisData exploration with correction for multiple testing and survival analysis from the time of diagnosis to time to death and time to first occurrence of severe pain as outcomes were carried out. The effect of seven complications on the modeled probability of dying within 2 yr after presenting with the complication was evaluated using logistic regression.Results and limitationsFeature exploration revealed novel phenotypes related to mPC outcome. Four complications (pleural effusion, severe anemia, severe or controlled pain, and bone fracture) predict the likelihood of death within 2 yr. Men with Gleason grade group 5 cancers developed severe pain sooner than those with lower-grade tumors. Surprisingly, neuroendocrine (NE) differentiation was frequently observed in the setting of high serum prostate-specific antigen (PSA) levels (≥30 ng/ml). In 4/33 patients, no controlled (requiring analgesics) or severe pain was detected, and strikingly, 14/15 metastatic sites studied in these men did not express NE markers, suggesting an inverse relationship between NE differentiation and pain in mPC. Intracranial subdural metastasis is common (36%) and is usually clinically undetected. Categorization of "skeletal-related events" complications used in recent studies likely obscures the understanding of spinal cord compression and fracture. Early death from prostate cancer was identified in a subgroup of men with a low longitudinal PSA bandwidth. Cachexia is common (body mass index <0.89 in 24/31 patients) but limited to the last year of life. Biomarker review identified 30 categories of mPC biomarkers in need of winnowing in future trials. All findings require validation in larger cohorts, preferably alongside data from this study.ConclusionsThe study identified novel outcome subgroups for future validation and provides "vision for mPC precision oncology 2020-2050" draft recommendations for future data collection and biomarker studies.Patient summaryTo better understand variation in metastatic prostate cancer behavior, we assembled and analyzed longitudinal clinical and autopsy records in 33 men. We identified novel outcomes, phenotypes, and aspects of disease burden to be tested and refined in future trials.

Project description:Qualitative and quantitative bone features were determined in nondecalcified and decalcified bone from 20 predetermined bone sites in each of 44 patients who died with castration-resistant prostate cancer (CRPC), some of which received bisphosphonate treatment (BP) in addition to androgen-deprivation therapy (ADT). Thirty-nine of the 44 patients (89%) had evidence of bone metastases. By histomorphometric analysis, these bone metastases were associated with a range of bone responses from osteoblastic to osteolytic with a wide spectrum of bone responses often seen within an individual patient. Overall, the average bone volume/tissue volume (BV/TV) was 25.7%, confirming the characteristic association of an osteoblastic response to prostate cancer bone metastasis when compared with the normal age-matched weighted mean BV/TV of 14.7%. The observed new bone formation was essentially woven bone, and this was a localized event. In comparing BV/TV at metastatic sites between patients who had received BP treatment and those who had not, there was a significant difference (28.6% versus 19.3%, respectively). At bone sites that were not invaded by tumor, the average BV/TV was 10.1%, indicating significant bone loss owing to ADT that was not improved (11%) in those patients who had received BPs. Surprisingly, there was no significant difference in the number of osteoclasts present at the metastatic sites between patients treated or not treated with BPs, but in bone sites where the patient had been treated with BPs, giant osteoclasts were observed. Overall, 873 paraffin-embedded specimens and 661 methylmethacrylate-embedded specimens were analyzed. Our results indicate that in CRPC patients, ADT induces serious bone loss even in patients treated with BP. Furthermore, in this cohort of patients, BP treatment increased BV and did not decrease the number of osteoclasts in prostate cancer bone metastases compared with bone metastases from patients who did not receive BP.

Project description:Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains and losses, including ETS gene family fusions, PTEN loss and androgen receptor (AR) amplification, which drive prostate cancer development and progression to lethal, metastatic castration-resistant prostate cancer (CRPC). However, less is known about the role of mutations. Here we sequenced the exomes of 50 lethal, heavily pre-treated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment-naive, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPCs (2.00 per megabase) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1 that define a subtype of ETS gene family fusion-negative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in approximately one-third of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Furthermore, we identified recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with the AR, which is required for AR-mediated signalling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signalling and increases tumour growth. Proteins that physically interact with the AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX (also known as KDM6A) and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signalling deregulated in prostate cancer, and prioritize candidates for future study.

Dataset Information

Frequent discordance between ERG gene rearrangement and ERG protein expression in a rapid autopsy cohort of patients with lethal, metastatic, castration-resistant prostate cancer.

Publications

Frequent discordance between ERG gene rearrangement and ERG protein expression in a rapid autopsy cohort of patients with lethal, metastatic, castration-resistant prostate cancer.

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