Alterations In Prostate Cancer Research Articles

Abstract 5420: Nuclear PTEN directly regulates androgen receptor activity in prostate cancer

Abstract The deletion of PTEN, a negative regulator of the PI3K pathway, is among the most frequent genomic alterations in prostate cancer. Attempts to target this alteration using PI3K pathway inhibitors, however, have yielded little clinical benefit for patients, and the function of PTEN loss in prostate cancer progression is not fully understood. Prostate cancers lacking PTEN are less responsive to therapy targeting the Androgen Receptor (AR), a dominant driver of prostate cancer growth, but how PTEN function interacts with AR activity is not clear. We used immunoblotting, immunoprecipitation, proximity ligation assay, chromatin immunoprecipitation, and transcriptome sequencing in cells with endogenous PTEN or PTEN knocked down to evaluate the interactions between these major factors in prostate cancer progression. We demonstrate that PTEN interacts with the Androgen Receptor in the nucleus, and PTEN can bind chromatin at known Androgen Response Elements. Stimulation of cells with androgen and other media components leads to accumulation of phosphorylated (inactive) PTEN, loss of nuclear PTEN, and decreased PTEN-AR interaction. Transcriptome analysis of cells with PTEN knocked down demonstrates increased expression of AR pathway genes, even in the absence of androgen stimulation. These results suggest nuclear PTEN may play a direct role in negative regulation of the Androgen Receptor, with implications for management of PTEN-negative prostate cancers. Citation Format: Yen T. Nguyen, Jose A. Rodriguez-Nieves, Qi Yang, David VanderWeele. Nuclear PTEN directly regulates androgen receptor activity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5420.

Abstract 4332: Meta-analysis of molecular features associated with aggressive prostate cancer

Abstract The TMPRSS2:ERG fusion is the most common genomic alteration in prostate cancer, occurring in 40-50% of primary tumors. The frequency of the ERG fusion remains between 40-50% in metastatic tumors, supporting previous findings that the fusion can drive tumor development, but is not sufficient to drive aggressive, lethal disease. Large -omic datasets collected over thousands of patient tumors, such as The Cancer Genome Atlas (TCGA), paired with outcomes present the raw data needed to associate genetic aberrations with markers of aggressive disease. Accordingly, we performed a meta-analysis of over 2,000 patient samples to identify combinations of -omic features associated with aggressive ERG fusion-positive and ERG fusion-negative prostate cancer. The data were collected from 8 independent, publicly available prostate cancer cohorts and cover range of disease phenotypes (e.g., neuroendocrine, castration resistance). Our analysis consisted of training univariate Cox regression models separately for single genomic or pairs of genomic features within each independent dataset. Based on the availability, we explored gene expression, mutation, and copy number alterations, all used to build separate models. We then combined models for a genomic feature across all datasets by weighting individual coefficients by the inverse of their squared error in a fixed effects model; final results are reported as corrected p-values. We compared and contrasted results from combined models within data type (i.e., only gene expression) to models integrating multiple data types. Interestingly, we find that the genomic features associated with aggressive disease differed based on ERG status. We report genomic loci that are altered in all patients, but associate with aggressive disease only in patients with an ERG fusion. We also report loci that co-occur or are mutually exclusive of the ERG fusion and associated with aggressiveness. For example, SPOP mutations are known to be mutually exclusive of ERG fusions. We report a finer stratification of patients with SPOP mutations based on biochemical relapse. Our results present a compressive meta-analysis of molecular features in prostate cancer and identify novel molecular subtypes associated with aggressive disease. Citation Format: James C. Costello, Rani Powers, Andrew Goodspeed, Scott D. Cramer. Meta-analysis of molecular features associated with aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4332.

Indel detection from DNA and RNA sequencing data with transIndel

BackgroundInsertions and deletions (indels) are a major class of genomic variation associated with human disease. Indels are primarily detected from DNA sequencing (DNA-seq) data but their transcriptional consequences remain unexplored due to challenges in discriminating medium-sized and large indels from splicing events in RNA-seq data.ResultsHere, we developed transIndel, a splice-aware algorithm that parses the chimeric alignments predicted by a short read aligner and reconstructs the mid-sized insertions and large deletions based on the linear alignments of split reads from DNA-seq or RNA-seq data. TransIndel exhibits competitive or superior performance over eight state-of-the-art indel detection tools on benchmarks using both synthetic and real DNA-seq data. Additionally, we applied transIndel to DNA-seq and RNA-seq datasets from 333 primary prostate cancer patients from The Cancer Genome Atlas (TCGA) and 59 metastatic prostate cancer patients from AACR-PCF Stand-Up- To-Cancer (SU2C) studies. TransIndel enhanced the taxonomy of DNA- and RNA-level alterations in prostate cancer by identifying recurrent FOXA1 indels as well as exitron splicing in genes implicated in disease progression.ConclusionsOur study demonstrates that transIndel is a robust tool for elucidation of medium- and large-sized indels from DNA-seq and RNA-seq data. Including RNA-seq in indel discovery efforts leads to significant improvements in sensitivity for identification of med-sized and large indels missed by DNA-seq, and reveals non-canonical RNA-splicing events in genes associated with disease pathology.

Epigenetic Changes Induced by Green Tea Catechins a re Associated with Prostate Cancer.

Prostate cancer is one of the most difficult cancers to treat especially when it becomes hormone resistant such as castrate resistant prostate cancer (CRPC) and subsequent metastatic CRPC. Apart from the genetic alterations in prostate cancer, epigenetic modifications also play an important role in the development and neoplastic progression of this disease. These include DNA methylation, histone modifications, and non-coding microRNAs. miRNAs are a novel class of small endogenous single-stranded non-coding RNAs of 19-25 nucleotides in length that typically silence gene expression. Considering the reversibility of epigenetic alterations in early carcinogenesis process, reversion (correction) of these modifications by green tea catechins could be a promising strategy for cancer chemoprevention and therapy. Recent evidence suggests that green tea catechins such as epigallocatechin gallate (EGCG) not only act as epigenetic modulators but can also modify miRNA expression and their target mRNAs, consistently contributing to the inhibition of prostate carcinogenesis. Various studies also indicate that several green tea polyphenols (GTPs) exert synergistic effects with other cancer chemotherapeutic agents. Therefore, the use of appropriate combinations of green tea catechins with the existing chemotherapeutics will lead to a reduction in side effects without decreasing the chemotherapeutic effects. This review will summarize the key results from recent studies detailing the effects of green tea catechins such as EGCG on epigenetic alterations and miRNA expression in prostate cancer.

Urinary Biomarkers for Prostate Cancer.

Urine may represent a convenient source of biomarkers for the early detection of Prostate Cancer (PCa) since it contains secreted prostatic products and exfoliated tumor cells. Furthermore, urine is easy to collect with non-invasive procedures which are repeatable. Several urinary biomarkers for PCa have been proposed in the past but only one (PCA3) has been approved for clinical use and even this is not widely utilized in the routine practice. Most of these, particularly the proteins, were abandoned due to lack of confirmation. DNA markers have been proposed but they are less suitable compared to other malignancies, such as bladder cancer due to the limited amount of DNA somatic alterations in PCa compared to gene fusions and pathway activations. RNA biomarkers are still the most promising and particularly miRNA and AMACR mRNA but the main weaknesses that prevented the full clinical implementation are the absence of a validated of the cut-off levels and the identification of consistent reference standards.

Identification of key pathways and genes with aberrant methylation in prostate cancer using bioinformatics analysis.

Prostate cancer (PCa), a multifocal clinically heterogeneous disease, is the most commonly diagnosed non-cutaneous neoplasm in men worldwide. The epigenome of PCa is a typical representation of catastrophic model of epigenetic alterations during tumorigenesis and its progression. Alterations in methylation patterns in tumor suppressors, cell cycle, oncogenes and metabolism-related genes are the most commonly observed epigenetic alterations in PCa. In this study, we have developed a computational strategy to identify methylated biomarker signature panels as potential targets of PCa by screening >160 genes reported to be epigenetically dysregulated, and shortlisted 26 differentially methylated genes (DMGs) that significantly contribute to oncogenesis. The gene ontology and functional enrichment analysis were performed, which showed that identified DMGs contribute to cellular and metabolic processes such as cell communication, cell cycle, response to drugs, apoptosis and p53 signaling. The top hub genes AR, CDH13, CDKN2A, DAPK1, GSTP1, CD44 and RASSF1 identified from protein–protein interaction network construction using Search Tool for the Retrieval of Interacting Genes contributed to hormonal response, inflammatory response, cell cycle, reactive oxygen species activity and receptor kinase activity, which are related to hallmarks of cancer as revealed by their functional enrichment analysis by Cytoscape. These genes were further scrutinized for CpG islands, transcription start sites and positions of methylated cytosines to study their methylation profiles. Our analysis revealed high negative correlation values between methylation frequencies and gene expressions of the hub genes, namely, AR, CDH13, CDKN2A, DAPK1, CD44, GSTP1 and RASSF1, which can be used as potential diagnostic biomarkers for PCa.

Clinical relevance of androgen receptor alterations in prostate cancer.

Prostate cancer (PC) remains a leading cause of cancer-related deaths among men worldwide, despite continuously improved treatment strategies. Patients with metastatic disease are treated by androgen deprivation therapy (ADT) that with time results in the development of castration-resistant prostate cancer (CRPC) usually established as metastases within bone tissue. The androgen receptor (AR) transcription factor is the main driver of CRPC development and of acquired resistance to drugs given for treatment of CRPC, while a minority of patients have CRPC that is non-AR driven. Molecular mechanisms behind epithelial AR reactivation in CRPC include AR gene amplification and overexpression, AR mutations, expression of constitutively active AR variants, intra-tumoural and adrenal androgen synthesis and promiscuous AR activation by other factors. This review will summarize AR alterations of clinical relevance for patients with CRPC, with focus on constitutively active AR variants, their possible association with AR amplification and structural rearrangements as well as their ability to predict patient resistance to AR targeting drugs. The review will also discuss AR signalling in the tumour microenvironment and its possible relevance for metastatic growth and therapy.

Whole-genome and Transcriptome Sequencing of Prostate Cancer Identify New Genetic Alterations Driving Disease Progression

BackgroundGlobal disparities in prostate cancer (PCa) incidence highlight the urgent need to identify genomic abnormalities in prostate tumors in different ethnic populations including Asian men. ObjectiveTo systematically explore the genomic complexity and define disease-driven genetic alterations in PCa. Design, setting, and participantsThe study sequenced whole-genome and transcriptome of tumor-benign paired tissues from 65 treatment-naive Chinese PCa patients. Subsequent targeted deep sequencing of 293 PCa-relevant genes was performed in another cohort of 145 prostate tumors. Outcome measurements and statistical analysisThe genomic alteration landscape in PCa was analyzed using an integrated computational pipeline. Relationships with PCa progression and survival were analyzed using nonparametric test, log-rank, and multivariable Cox regression analyses. Results and limitationsWe demonstrated an association of high frequency of CHD1 deletion with a low rate of TMPRSS2-ERG fusion and relatively high percentage of mutations in androgen receptor upstream activator genes in Chinese patients. We identified five putative clustered deleted tumor suppressor genes and provided experimental and clinical evidence that PCDH9, deleted/loss in approximately 23% of tumors, functions as a novel tumor suppressor gene with prognostic potential in PCa. Furthermore, axon guidance pathway genes were frequently deregulated, including gain/amplification of PLXNA1 gene in approximately 17% of tumors. Functional and clinical data analyses showed that increased expression of PLXNA1 promoted prostate tumor growth and independently predicted prostate tumor biochemical recurrence, metastasis, and poor survival in multi-institutional cohorts of patients with PCa. A limitation of this study is that other genetic alterations were not experimentally investigated. ConclusionsThere are shared and salient genetic characteristics of PCa in Chinese and Caucasian men. Novel genetic alterations in PCDH9 and PLXNA1 were associated with disease progression. Patient summaryWe reported the first large-scale and comprehensive genomic data of prostate cancer from Asian population. Identification of these genetic alterations may help advance prostate cancer diagnosis, prognosis, and treatment.

Genomes of early onset prostate cancer.

Prostate cancer is a disease of the elderly but a clinically relevant subset occurs early in life. In the current review, we discuss recent findings and the current understanding of the molecular underpinnings associated with early-onset prostate cancer (PCa) and the evidence supporting age-specific differences in the cancer genomes. Recent surveys of PCa patient cohorts have provided novel age-dependent links between germline and somatic aberrations which points to differences in the molecular cause and treatment options. Identifying the earliest molecular alterations in PCa can provide insight into the cause of the disease and biomarkers for patient risk stratification. Genomic aberrations of early-onset PCas display several patterns distinct from late-onset PCa genomes, suggesting age-dependent pathomechanisms involving alterations in the androgen receptor pathway.

Molecular alterations in prostate cancer and association with MRI features.

Multiparametric magnetic resonance imaging (mpMRI) has been increasingly used for prostate cancer (PCa). Recent studies identified distinct molecular subclasses of PCa with recurrent genomic alterations. However, the associations between molecular alterations in PCa and characteristics on mpMRI are unknown. Therefore, the objective of this study was to investigate recurrent molecular alterations in PCa and their associations with mpMRI features. Sixty-two PCa nodules >0.5 cm had a preoperative mpMRI. Nodules were evaluated for ERG rearrangement, PTEN deletion, SPINK1 overexpression, SPOP mutation and CHD1 deletion. Each PCa focus was matched to the corresponding location on mpMRI. Lesions were scored by single observer according to the PI-RADSv2 scale. Of the 62 nodules, 22 (35.5%) were ERG positive, 6 (9.7%) had SPINK1 overexpression, 6 (9.7%) had SPOP mutations, 4 (6.5%) had CHD1 deletions and 1 (1.6%) had PTEN deletion. All of the nodules with CHD1 deletions were not visible on mpMRI (P=0.037). All of the nodules with SPINK1 overexpression were visible on mpMRI, although the association was not statistically significant (P=0.06). There were no significant associations between any molecular alteration with the severity of the PI-RADS scores (all P>0.05). This investigation represents the first description of an association between recurrent molecular alterations and the characterization of PCa nodules on mpMRI. This study can be considered hypothesis-generating for future studies to rigorously evaluate the association of specific PCa molecular subclasses with imaging features and potentially define specific subsets of PCa for which the utility of MRI is higher or lower.

Abstract 3392: Genomic analysis of prostate cancer in Korean men

Abstract Prostate cancer currently has the fifth highest incidence rate in Korean males, and is the most common cancer in western males. Prostate cancer is the second most common malignancy in men worldwide, and is responsible for approximately 250,000 cancer-related deaths annually. The search for accurate biomarkers and characterization of prostate cancer is critical for evolution of accurate management of prostate cancer. Previous studies have identified that several genomic alterations in prostate cancer including TMPRSS2-ERG fusion, PTEN deletion and SPOP single nucleotide variants (SNVs), the majority of which are from western population. In order to investigate the somatic mutations of Korean prostate cancers, we performed whole exome sequencing on 51 prostate cancer patient’s tumor tissues, and matched normal tissue. For the accurate detections of structural variations, we additionally performed whole genome sequencing on 9 matched pairs (tumor, normal). A total of 738 somatic non-silent variants affecting 692 distinct genes were identified. In addition to already known genes such as SPOP, FOXA1, TP53 and PTEN, we also found previously uncharacterized genes such as GRIN2A, LRP1, FNDC1 and LRP1B. Of the 40 mutated genes across multiple cases, missense SNVs of SPOP (10/60 cases, 16.7%) were the most frequent, followed by missense and splice-site SNVs of GRIN2A (5/60 cases, 8.3%). Mutations in low-density lipoprotein-related protein encoded by LRP1 and LRP1B affected considerable portion of all cases (7/60, 11.7%), describe the probable relation between lipid metabolism and prostate cancer. We found TMPRSS2-ERG fusion in 4 of 9 whole genome samples. Moreover, 5 samples had 8p whole arm deletion, which is found frequent in western prostate cancers. As a result, we describe the genomic patterns of genetic variations and structural variations involved in prostate cancer of Korean population. Citation Format: Se Song Jang, Min Jung Kim, Dong Wan Hong, Jae Young Joung, Sung Han Kim, Kang Hyun Lee, Weon Seo Park, Jong-Il Kim. Genomic analysis of prostate cancer in Korean men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3392. doi:10.1158/1538-7445.AM2017-3392

Abstract 2702: Mutations of SPOP, FOXA1 and IDH1 are associated with prostate cancer metastasis and biochemical outcomes

Abstract Recent genomic studies have shed light on cataloging genomic alterations in prostate cancer. Mechanistic studies allow the use of this information to subclassify the heterogeneous prostate tumors for optimized treatment planning. Speckle-Type POZ Protein (SPOP), Forkhead Box Protein A1 (FOXA1) and Isocitrate Dehydrogenase 1 (IDH1) are among the genes that show frequent point mutations in primary prostate cancers. However, the clinical significance of these gene mutations in cancer patients is less clear. To determine the whether SPOP, FOXA1 and IDH1 mutations are associated with clinical outcomes in prostate cancer, we pyro-sequenced the three genes in prostate cancer patients and evaluated the clinical and prognostic significance. 198 patients from the first hospital of Xi’An Jiaotong University (China) were analyzed. All patients were newly diagnosed with prostate cancer from January 2010 to December 2015. No patient was lost to follow-up. The average follow-up time after the primary diagnosis was 27 months. The Fisher’s exact tests were used to compare categorical data. The risk of metastasis among patients with SPOP, FOXA1 and IDH1 mutations was evaluated using univariate and multivariate logistic regression models. The prognostic significance of clinical and gene mutations was determined using multivariate Cox regression analysis. SPOP mutations were found in 16 patients (8.1%), with all of the mutations clustered in the substrate-binding MATH domain. FOXA1 mutationswere found in nine patients (4.5%), and were clustered in the Forkhead domain. IDH1 mutations were detected in three patients (1.5%). Mutation frequencies of SPOP, FOXA1 and IDH1 were associated with prostate-specific antigen (PSA), a biochemical marker of prostate tumor presence/risk which is decided by Gleason Score, T stage and PSA level, along with prostate cancer PSA failure and metastasis. Among patients with SPOP mutation, 56.3% showed metastasis at the time of diagnosis of primary cancer, compared to only 11.5% of patients with wild-type SPOP. Similarly, the probabilities of FOXA1 and IDH1 mutations with metastasis were approximately 44.4% and 66.7% versus 13.8% and 14.4%, respectively, comparing to their wild-type counterparts. The metastasis risk for patients with SPOP mutation was 1.27 times of the SPOP wild-type patients (P = 0.003). We also found that patients with SPOP (P < 0.0001) and FOXA1 (P = 0.0403) mutations showed higher risk of PSA failure compared with wild-type. The PSA failure risk for patients with SPOP mutation was 35.49 times of the SPOP wild-type patients. In contrast, IDH1 mutation was not associated with PSA failure (P = 0.054). Multivariate analyses demonstrate that SPOP mutation is an independent factor that is associated with prostate cancer metastasis and PSA failure recurrence. These findings underscore the clinical significance for profiling SPOP, FOXA1 and IDH1. Note: This abstract was not presented at the meeting. Citation Format: Jinlu Ma, Suxia Han, Xin Sui, Wenyan Lu, Yonghe Li, Bo Xu. Mutations of SPOP, FOXA1 and IDH1 are associated with prostate cancer metastasis and biochemical outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2702. doi:10.1158/1538-7445.AM2017-2702

Abstract 4435: Exosomal miR-3622a as prognostic marker in prostate cancer

Abstract Loss of chromosome (chr) 8p21 is a frequent genomic alteration in prostate cancer (PCa). Genomic deletions of this region increase significantly with tumor grade and are associated with tumor progression and poor prognosis. A common region of loss of heterozygosity (LOH) has been mapped to the chr8p21 locus that primarily harbors prostate-specific NKX3.1 homeobox gene. We recently demonstrated that this frequently deleted locus is associated with a cluster of microRNA genes- miR-3622a/b- that are lost in prostate cancer and play an important mechanistic role in PCa progression and metastasis. MicroRNA expression profiling in microdissected human PCa clinical tissues showed that miR-3622a/b expression is widely downregulated and is correlated with poor survival outcome in prostate cancer. Our analyses suggested that miR-3622a has potential as a prognostic and diagnostic marker for prostate cancer. Extending these findings, we explored the prognostic potential of serum miR-3622a in prostate cancer patients. Since exosomes provide an important source of non-invasive, circulating biomarkers and represent an enriched source of microRNAs for biomarker profiling, we profiled the microRNA content of exosomes derived from sera of prostate cancer patients. In a pilot study, we profiled exosomal miRNAs from a training cohort of individuals with benign prostate hyperplasia (BPH), an indolent form of PCa or aggressive metastatic PCa. Exosomes were isolated from sera of prostate cancer patients and integrity of exosomal preparations was confirmed by nanoparticle tracking analysis and Western blot analyses for exosomal markers. Expression analyses of exosomal miR-3622a expression showed that this miRNA is enriched in exosomes. Higher levels of miR-3622a were significantly associated with tumor stage and lymph node metastasis in a cohort of prostate cancer clinical specimens. Further, ROC (Receiver Operating Characteristic) analyses showed that exosomal miR-3622a expression can be a single significant parameter to discriminate between BPH and prostate cancer. Overall, our data suggests that exosomal miR-3622a is a promising prognostic biomarker for prostate cancer. patients. Citation Format: Thao Yang, Divya Bhagirath, Kirandeep Sekhon, Nathan Bucay, Shahana Majid, Varahram Shahryari, Marisa Shiina, Yutaka Hashimoto, Priyanka Kulkarni, Pritha Dasgupta, Mitsuho Imai-Sumida, Soichiro Yamamura, Z Laura Tabatabai, Kirsten Greene, Yuichiro Tanaka, Rajvir Dahiya, Guoren Deng, Sharanjot Saini. Exosomal miR-3622a as prognostic marker in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4435. doi:10.1158/1538-7445.AM2017-4435

Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognosticvalue. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.

Identification of novel fumarate hydratase gene alterations in prostate cancer.

11585 Background: Fumarate hydratase (FH), an enzyme involved in the Krebs cycle, plays a crucial role in the generation of energy and oxygenation of cells. Genomic alterations (GAs) of FH, a tumor suppressor gene, have been shown to cause chronic hypoxia that encourages tumor formation and have been linked to hereditary leiomyomatosis and renal cell cancer. Only few reports have associated FH mutations with other cancers, and none in prostate cancer. Methods: Identification of an FH V435M pathogenic alteration, which likely changes fumarate binding kinetics, in a prostate cancer patient, with negative family history for renal cancer and cutaneous leiomyomatosis, led to review of a database of 1781 prostate cancer patients, whose tissue was assayed by hybrid-capture based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA: base substitutions, indels, amplifications, copy number alterations, fusions/rearrangements) and targeted therapy opportunities. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb sequenced DNA and reported as mutations/Mb. Results: Profiling identified 49 prostate adenocarcinoma patients (3%) with FH gene alterations, 2 of which harbored the V435M GA identified in the original prostate patient. Ten of 40 alterations were H476_k477 insertions, in the C terminus domain, and 14 were amplifications. The rest were variants of unknown significance (VUS). Conclusions: A FH GA, known to impact other cancers, found in a prostate cancer, led to the discovery of a frequency that suggests deregulation of metabolic pathway activation may contribute to prostate cancer pathogenesis for a subset of patients. The somatic FH GA’s are likely to be substantially more common than germline mutations, and identifying metabolic-enzyme mutations that are pathogenic in prostate cancer could lead to pharmacologic manipulations that are more effective and less toxic than existing therapies. No FDA approved therapies currently exist for this patient’s tumor type nor of any other tumor type with FH GA’s. In our case, alterations in the C-terminal binding domain of FH might inform drug development.

Exploiting Epigenetic Alterations in Prostate Cancer.

Prostate cancer affects an increasing number of men worldwide and is a leading cause of cancer-associated deaths. Beside genetic mutations, many epigenetic alterations including DNA and histone modifications have been identified in clinical prostate tumor samples. They have been linked to aberrant activity of enzymes and reader proteins involved in these epigenetic processes, leading to the search for dedicated inhibitory compounds. In the wake of encouraging anti-tumor efficacy results in preclinical models, epigenetic modulators addressing different targets are now being tested in prostate cancer patients. In addition, the assessment of microRNAs as stratification biomarkers, and early clinical trials evaluating suppressor microRNAs as potential prostate cancer treatment are being discussed.

Predicting Prostate Cancer Progression as a Function of ETS-related Gene Status, Race, and Obesity in a Longitudinal Patient Cohort

BackgroundETS-related gene (ERG) oncogenic activation is the most common genomic alteration in prostate cancer (CaP) although it occurs less frequently in African American (AA) versus Caucasian (CA) patients, and the potential role of ERG as a prognostic marker has not been confirmed. ObjectiveThis study was conducted to confirm strong racial variation in the prevalence of ERG oncoprotein expression and to examine ERG oncoprotein expression, race, and body mass index as independent and joint predictors of CaP biochemical recurrence (BCR) following radical prostatectomy (RP). Design, setting, and participantsA retrospective cohort study of CA and AA CaP patients enrolled at Walter Reed National Military Medical Center, who donated clinically annotated, whole-mounted, prostatectomy specimens between 1994 and 2014 following RP, was conducted. Outcome measurements and statistical analysisKaplan–Meier (KM) estimation curves and multivariable Cox proportional hazards models were used to examine time to BCR as a function of ERG status, patient race, and obesity. Results and limitationsAmong 930 eligible patients (36.1% AA and 63.9% CA), with 155 (16.7%) BCR events and a median follow-up time of 5.1 yr, ERG oncoprotein expression was significantly less prevalent in index tumors of AA versus CA patients (23.2% vs 49.3%; p<0.0001). KM curves showed significantly poorer BCR-free survival for CA patients with ERG-negative index tumors but not for AA patients. Race-stratified multivariable analyses revealed a significant association between ERG-negative index tumors and poorer BCR-free survival among CA patients (hazards ratio=1.67, confidence interval=1.07, 2.61; p=0.024). Less heterogeneity in ERG expression among AA patients may reduce the ability to show its association with BCR. ConclusionsStriking racial variation in ERG oncoprotein expression was confirmed. A novel observation was the importance of index tumor ERG-negative status in predicting CaP progression for CA patients. Patient summaryETS-related gene (ERG) typing of tumors may be useful in prognosticating prostate cancer aggressiveness.

Comprehensive genomic sequencing of prostate sarcomatoid carcinoma tumors identifies differences in genomic alterations compared to prostate adenocarcinoma tumors.

226 Background: Sarcomatoid carcinoma of the prostate is a rare variant of prostatic cancer and has a significantly worse prognosis. The genomic features underpinning this rare subtype of malignancy are not well understood, and at present, there are no effective therapies. Methods: Tissue from 1417 prostate cancer patients was assayed by hybrid-capture based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA: base substitutions, indels, amplifications, copy number alterations, fusions/rearrangements) and targeted therapy opportunities. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb sequenced DNA and reported as mutations/Mb. Results: Profiling identified different patterns in GAs between prostate adenocarcinoma (1409) and prostate sarcomatoid carcinoma (8) (table), most notably in the commonly identified alterations in prostate cancers: TP53, RB1, and TMPRSS2-ERG. Additionally, the PI3K/mTOR pathway was altered in 50% of the sarcomatoid carcinoma cohort. None of the sarcomatoid carcinoma patients had a high TMB, while 4% of the prostate adenocarcinomas had TMB greater than 19 mutations/Mb. The sarcomatoid carcinoma cohort also had on average 8 GAs, while the prostate adenocarcinoma cohort had an average of 13 GAs. Conclusions: Genomic profiles of tumors from patients with prostate cancers reveal that those with sarcomatoid carcinoma features are more likely to have genomic alterations in TP53, RB1, and TMPRSS2 but fewer overall GA’s. Based on rearrangements and the sarcoma profile, utilization of a broad CGP panel that includes analysis of a larger panel of rearrangements identifies more commonly rearranged genes that would not be identified in non-comprehensive panels that do not evaluate these rearrangements. These findings may contribute to a better understanding of the oncogenesis of sarcomatoid prostate carcinoma and for defining novel systemic treatment options. [Table: see text]

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Prostate Cancer Prognosis Defined by the Combined Analysis of 8q, PTEN and ERG

Overtreatment is a major concern in men diagnosed with prostate cancer. The aim of this study was to evaluate the combined prognostic role of three frequent molecular alterations in prostate cancer, namely relative 8q gain, ERG overexpression, and loss of PTEN expression, in a series of 136 patients with prostate cancer treated with prostatectomy and with a long follow-up. Fluorescent in situ hybridization was used to detect the relative copy number of 8q and immunohistochemistry was used for quantitative assessment of ERG and PTEN expression. During a median follow-up period of 117.8 months, 66 (49%) patients had disease recurrence. Relative 8q gain, ERG overexpression, and loss of PTEN expression were observed in 18%, 56%, and 33% of the cases, respectively. No association with patient recurrence-free survival was found for relative 8q gain or ERG overexpression on their own, whereas loss of PTEN expression was associated with worse recurrence-free survival (P=.006). Interestingly, in the subgroup of patients with normal PTEN expression, we found that the combined relative 8q gain/ERG overexpression is associated with high risk of recurrence (P=.008), suggesting that alternative mechanisms exist for progression into clinically aggressive disease. Additionally, in intermediate-risk patients with normal PTEN expression in their tumors, the combination of 8q gain/ERG overexpression was associated with a poor recurrence-free survival (P<.001), thus indicating independent prognostic value. This study shows that the combined analysis of 8q, ERG and PTEN contributes to an improved clinical outcome stratification of prostate cancer patients treated with radical prostatectomy.