Prostate cancer is a clinically heterogeneous disease, with some men having indolent disease that can safely be observed, while others have aggressive, lethal disease. Over the past decade, ...researchers have begun to unravel some of the genomic heterogeneity that contributes to these varying clinical phenotypes. Distinct molecular sub-classes of prostate cancer have been identified, and the uniqueness of these sub-classes has been leveraged to predict clinical outcomes, design novel biomarkers for prostate cancer diagnosis, and develop novel therapeutics. Recent work has also elucidated the temporal and spatial heterogeneity of prostate cancer, helping us understand disease pathogenesis, response to therapy, and progression. New genomic techniques have provided us with a window into the remarkable clinical and genomic heterogeneity of prostate cancer, and this new perspective will increasingly impact patient care.
Comprehensive genomic characterization of prostate cancer has identified recurrent alterations in genes involved in androgen signaling, DNA repair, and PI3K signaling, among others. However, larger ...and uniform genomic analysis may identify additional recurrently mutated genes at lower frequencies. Here we aggregate and uniformly analyze exome sequencing data from 1,013 prostate cancers. We identify and validate a new class of E26 transformation-specific (ETS)-fusion-negative tumors defined by mutations in epigenetic regulators, as well as alterations in pathways not previously implicated in prostate cancer, such as the spliceosome pathway. We find that the incidence of significantly mutated genes (SMGs) follows a long-tail distribution, with many genes mutated in less than 3% of cases. We identify a total of 97 SMGs, including 70 not previously implicated in prostate cancer, such as the ubiquitin ligase CUL3 and the transcription factor SPEN. Finally, comparing primary and metastatic prostate cancer identifies a set of genomic markers that may inform risk stratification.
To elucidate potential biomarkers or mechanistic principles involved with the gut microbiota and its impact on prostate cancer pathogenesis.
We performed a prospective case-control pilot study ...evaluating the gut microbiome of 20 men with either benign prostatic conditions (n = 8) or intermediate or high risk clinically localized prostate cancer (Gleason ≥4 + 3 cN0M0) (n = 12) undergoing care at tertiary referral center from September 1, 2015 to March 1, 2016. Key exclusion criteria included recent antibiotic use, significant gastrointestinal disorders, hormonal or systemic therapy for prostate cancer. Computational genomics analysis was performed on collected stool samples using MetaPhlAn2 and HUMAnN2 platforms. Linear discriminant analysis effect size method was used to support high-dimensional class comparisons to find biologically relevant features. Kruskal-Wallis sum-rank test was used to detect features with significant differential abundance with respect to class, with biological consistency investigated using a set of pairwise tests among subclasses using the Wilcoxon rank-sum test, both to an α ≤0.05.
Higher relative abundance of Bacteriodes massiliensis was seen in prostate cancer cases compared to controls. Faecalibacterium prausnitzii and Eubacterium rectalie had higher relative abundance among controls. Biologically significant differences were also found in relative gene, pathway, and enzyme abundance.
Biologically significant differences exist in the gut microbial composition of men with prostate cancer compared to benign controls. These differences may play a role in the pathobiology of prostate cancer, and warrant further exploration.
Mutations in the transcription factor FOXA1 define a unique subset of prostate cancers but the functional consequences of these mutations and whether they confer gain or loss of function is unknown
. ...Here, by annotating the landscape of FOXA1 mutations from 3,086 human prostate cancers, we define two hotspots in the forkhead domain: Wing2 (around 50% of all mutations) and the highly conserved DNA-contact residue R219 (around 5% of all mutations). Wing2 mutations are detected in adenocarcinomas at all stages, whereas R219 mutations are enriched in metastatic tumours with neuroendocrine histology. Interrogation of the biological properties of wild-type FOXA1 and fourteen FOXA1 mutants reveals gain of function in mouse prostate organoid proliferation assays. Twelve of these mutants, as well as wild-type FOXA1, promoted an exaggerated pro-luminal differentiation program, whereas two different R219 mutants blocked luminal differentiation and activated a mesenchymal and neuroendocrine transcriptional program. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) of wild-type FOXA1 and representative Wing2 and R219 mutants revealed marked, mutant-specific changes in open chromatin at thousands of genomic loci and exposed sites of FOXA1 binding and associated increases in gene expression. Of note, ATAC-seq peaks in cells expressing R219 mutants lacked the canonical core FOXA1-binding motifs (GTAAAC/T) but were enriched for a related, non-canonical motif (GTAAAG/A), which was preferentially activated by R219-mutant FOXA1 in reporter assays. Thus, FOXA1 mutations alter its pioneering function and perturb normal luminal epithelial differentiation programs, providing further support for the role of lineage plasticity in cancer progression.
Abstract Context For more precise, personalized care in prostate cancer (PC), a new classification based on molecular features relevant for prognostication and treatment stratification is needed. ...Genomic aberrations in the DNA damage repair pathway are common in PC, particularly in late-stage disease, and may be relevant for treatment stratification. Objective To review current knowledge on the prevalence and clinical significance of aberrations in DNA repair genes in PC, particularly in metastatic disease. Evidence acquisition A literature search up to July 2016 was conducted, including clinical trials and preclinical basic research studies. Keywords included DNA repair, BRCA, ATM, CRPC, prostate cancer, PARP, platinum, predictive biomarkers , and hereditary cancer. Evidence synthesis We review how the DNA repair pathway is relevant to prostate carcinogenesis and progression. Data on how this may be relevant to hereditary cancer and genetic counseling are included, as well as data from clinical trials of PARP inhibitors and platinum therapeutics in PC. Conclusions Relevant studies have identified genomic defects in DNA repair in PCs in 20–30% of advanced castration-resistant PC cases, a proportion of which are germline aberrations and heritable. Phase 1/2 clinical trial data, and other supporting clinical data, support the development of PARP inhibitors and DNA-damaging agents in this molecularly defined subgroup of PC following success in other cancer types. These studies may be an opportunity to improve patient care with personalized therapeutic strategies. Patient summary Key literature on how genomic defects in the DNA damage repair pathway are relevant for prostate cancer biology and clinical management is reviewed. Potential implications for future changes in patient care are discussed.
Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe a mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional ...expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia and invasive, poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP drove increased proliferation and a transcriptional signature consistent with human prostate cancer. Using these models and human prostate cancer samples, we show that SPOP mutation activates both PI3K/mTOR and androgen receptor signaling, effectively uncoupling the normal negative feedback between these two pathways.
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•Mutations in SPOP are driver events resulting in prostate tumorigenesis in the mouse•SPOP mutation activates PI3K/mTOR signaling through upregulation of SRC3 (NCOA3)•SPOP mutation maintains AR signaling against PI3K/mTOR-mediated negative feedback•Mutant SPOP upregulates a network of AR-associated transcription factors
Blattner et al. develop a mouse model and use it to demonstrate that human SPOP mutation can drive prostate tumorigenesis through coordinate deregulation of both PI3K/mTOR and AR pathways. The study provides insights to both unique and common features of molecular subtypes of human prostate cancer.
The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play ...critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3
earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.
Abstract Context Biomarker-driven cancer therapy, also referred to as precision oncology, has received increasing attention for its promise of improving patient outcomes by defining subsets of ...patients more likely to respond to various therapies. Objective In this collaborative review article, we examine recent literature regarding biomarker-driven therapeutics in urologic oncology, to better define the state of the field, explore the current evidence supporting utility of this approach, and gauge potential for the future. Evidence acquisition We reviewed relevant literature, with a particular focus on recent studies about targeted therapy, predictors of response, and biomarker development. Evidence synthesis The recent advances in molecular profiling have led to a rapid expansion of potential biomarkers and predictive information for patients with urologic malignancies. Across disease states, distinct molecular subtypes of cancers have been identified, with the potential to inform choices of management strategy. Biomarkers predicting response to standard therapies (such as platinum-based chemotherapy) are emerging. In several malignancies (particularly renal cell carcinoma and castration-resistant prostate cancer), targeted therapy against commonly altered signaling pathways has emerged as standard of care. Finally, targeted therapy against alterations present in rare patients (less than 2%) across diseases has the potential to drastically alter patterns of care and choices of therapeutic options. Conclusions Precision medicine has the highest potential to impact the care of patients. Prospective studies in the setting of clinical trials and standard of care therapy will help define reliable predictive biomarkers and new therapeutic targets leading to real improvement in patient outcomes. Patient summary Precision oncology uses molecular information (DNA and RNA) from the individual and the tumor to match the right patient with the right treatment. Tremendous strides have been made in defining the molecular underpinnings of urologic malignancies and understanding how these predict response to treatment—this represents the future of urologic oncology.
Deletion of the gene encoding the chromatin remodeler CHD1 is among the most common alterations in prostate cancer (PCa); however, the tumor-suppressive functions of CHD1 and reasons for its ...tissue-specific loss remain undefined. We demonstrated that CHD1 occupied prostate-specific enhancers enriched for the androgen receptor (AR) and lineage-specific cofactors. Upon CHD1 loss, the AR cistrome was redistributed in patterns consistent with the oncogenic AR cistrome in PCa samples and drove tumor formation in the murine prostate. Notably, this cistrome shift was associated with a unique AR transcriptional signature enriched for pro-oncogenic pathways unique to this tumor subclass. Collectively, these data credential CHD1 as a tumor suppressor in the prostate that constrains AR binding/function to limit tumor progression.
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•CHD1 acts as a prostate-specific tumor suppressor in vivo•CHD1 regulates AR occupancy at a subset of lineage-specific enhancers•Loss of CHD1 redistributes the AR cistrome to favor oncogenic AR-driven pathways
Augello et al. show that CHD1 binds prostate-specific enhancers enriched for the androgen receptor (AR). Upon CHD1 loss, which occurs often in prostate cancer (PCa), the AR cistrome changes to be consistent with that in PCa and is associated with an AR transcriptional signature unique to this subclass of PCa.
Abstract Context Prostate cancer (PCa) is a clinically heterogeneous disease with marked variability in patient outcomes. Molecular characterization has revealed striking mutational heterogeneity ...that may underlie the variable clinical course of the disease. Objective In this review, we discuss the common genomic alterations that form the molecular basis of PCa, their functional significance, and the potential to translate this knowledge into patient care. Evidence acquisition We reviewed the relevant literature, with a particular focus on recent studies on somatic alterations in PCa. Evidence synthesis Advances in sequencing technology have resulted in an explosion of data regarding the mutational events underlying the development and progression of PCa. Heterogeneity is the norm; few abnormalities in specific genes are highly recurrent, but alterations in certain signaling pathways do predominate. These alterations include those in pathways known to affect tumorigenesis in a wide spectrum of tissues, such as the phosphoinositide 3-kinase/phosphatase and tensin homolog/Akt pathway, cell cycle regulation, and chromatin regulation. Alterations more specific to PCa are also observed, particularly gene fusions of ETS transcription factors and alterations in androgen signaling. Mounting data suggest that PCa can be subdivided based on a molecular profile of genetic alterations. Conclusions Major advances have been made in cataloging the genomic alterations in PCa and understanding the molecular mechanisms underlying the disease. These findings raise the possibility that PCa could soon transition from being a poorly understood, heterogeneous disease with a variable clinical course to being a collection of homogenous subtypes identifiable by molecular criteria, associated with distinct risk profiles, and perhaps amenable to specific management strategies or targeted therapies.
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