The transition from castration-resistant prostate adenocarcinoma (CRPC) to neuroendocrine prostate cancer (NEPC) has emerged as an important mechanism of treatment resistance. NEPC is associated with ...overexpression and gene amplification of MYCN (encoding N-Myc). N-Myc is an established oncogene in several rare pediatric tumors, but its role in prostate cancer progression is not well established. Integrating a genetically engineered mouse model and human prostate cancer transcriptome data, we show that N-Myc overexpression leads to the development of poorly differentiated, invasive prostate cancer that is molecularly similar to human NEPC. This includes an abrogation of androgen receptor signaling and induction of Polycomb Repressive Complex 2 signaling. Altogether, our data establishes N-Myc as an oncogenic driver of NEPC.
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•N-Myc drives the NEPC phenotype and associated molecular program•N-Myc abrogates AR signaling, which results in enhanced AKT activity•N-Myc redirects EZH2 activity and sensitizes cells to EZH2 inhibitors•N-Myc interacts with Aurora-A, which facilitates N-Myc target gene expression
Dardenne et al. demonstrate that N-Myc overexpression in pre-clinical models drives aggressive prostate cancer that mimics human neuroendocrine prostate cancer, including reduced AR signaling and enhanced PRC2 target gene repression, and sensitizes cells to an Aurora-A inhibitor and EZH2 SET domain inhibitors.
Metastasis-the disseminated growth of tumours in distant organs-underlies cancer mortality. Breast-to-brain metastasis (B2BM) is a common and disruptive form of cancer and is prevalent in the ...aggressive basal-like subtype, but is also found at varying frequencies in all cancer subtypes. Previous studies revealed parameters of breast cancer metastasis to the brain, but its preference for this site remains an enigma. Here we show that B2BM cells co-opt a neuronal signalling pathway that was recently implicated in invasive tumour growth, involving activation by glutamate ligands of N-methyl-D-aspartate receptors (NMDARs), which is key in model systems for metastatic colonization of the brain and is associated with poor prognosis. Whereas NMDAR activation is autocrine in some primary tumour types, human and mouse B2BM cells express receptors but secrete insufficient glutamate to induce signalling, which is instead achieved by the formation of pseudo-tripartite synapses between cancer cells and glutamatergic neurons, presenting a rationale for brain metastasis.
Altered bone structure and function contribute to the high rates of fractures in dialysis patients compared to the general population. Fracture events may increase the risk of subsequent adverse ...clinical outcomes. Here we assessed the incidence of post-fracture morbidity and mortality in an international cohort of 34,579 in-center hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS). We estimated country-specific rates of fractures requiring a hospital admission and associated length of stay in the hospital. Incidence rates of death and of a composite event of death/rehospitalization were estimated for 1 year after fracture. Overall, 3% of participants experienced a fracture. Fracture incidence varied across countries, from 12 events/1000 patient-years (PY) in Japan to 45/1000 PY in Belgium. In all countries, fracture rates were higher in the hemodialysis group compared to those reported for the general population. Median length of stay ranged from 7 to 37 days in the United States and Japan, respectively. In most countries, postfracture mortality rates exceeded 500/1000 PY and death/rehospitalization rates exceeded 1500/1000 PY. Fracture patients had higher unadjusted rates of death (3.7-fold) and death/rehospitalization (4.0-fold) compared to the overall DOPPS population. Mortality and hospitalization rates were highest in the first month after the fracture and declined thereafter. Thus, the high frequency of fractures and increased adverse outcomes following a fracture pose a significant health burden for dialysis patients. Fracture prevention strategies should be identified and applied broadly in nephrology practices.
Animal models, particularly mouse models, play a central role in the study of the etiology, prevention, and treatment of human prostate cancer. While tissue culture models are extremely useful in ...understanding the biology of prostate cancer, they cannot recapitulate the complex cellular interactions within the tumor microenvironment that play a key role in cancer initiation and progression. The National Cancer Institute (NCI) Mouse Models of Human Cancers Consortium convened a group of human and veterinary pathologists to review the current animal models of prostate cancer and make recommendations about the pathologic analysis of these models. More than 40 different models with 439 samples were reviewed, including genetically engineered mouse models, xenograft, rat, and canine models. Numerous relevant models have been developed over the past 15 years, and each approach has strengths and weaknesses. Analysis of multiple genetically engineered models has shown that reactive stroma formation is present in all the models developing invasive carcinomas. In addition, numerous models with multiple genetic alterations display aggressive phenotypes characterized by sarcomatoid carcinomas and metastases, which is presumably a histologic manifestation of epithelial-mesenchymal transition. The significant progress in development of improved models of prostate cancer has already accelerated our understanding of the complex biology of prostate cancer and promises to enhance development of new approaches to prevention, detection, and treatment of this common malignancy.
Purpose Limited information is available on radical prostatectomy findings in men with intraductal carcinoma of the prostate on needle core biopsy in the absence of invasive prostate cancer. ...Materials and Methods From the consulting files of one of us we identified 83 men in whom biopsy showed only intraductal prostate cancer. Followup was available in 66 cases. We reviewed slides in 21 radical prostatectomy cases. Results Treatment was radical prostatectomy in 23 men, radiation therapy in 15, hormone therapy in 8 and radiation plus hormone therapy in 15 while 5 underwent no treatment or repeat biopsy. Of the 21 radical prostatectomies available for review findings revealed pathological stage pT3a in 8 (38%), pT3b in 3 (13%), pT2 in 8 (38%) and intraductal carcinoma without identifiable invasive cancer in 2 (10%). One patient with pT3a had a positive lymph node at surgery. Average Gleason score was 7.9. Three patients (14%) experienced post-prostatectomy biochemical failure and another (5%) had bone metastases 2.5 years after prostatectomy. In 15 prostatectomies (71%) there was extensive intraductal carcinoma, defined as greater than 10% of tumor being intraductal, including the 2 cases of intraductal carcinoma only. Of the 19 prostatectomies with invasive adenocarcinoma 16 (84%) were conventional acinar adenocarcinoma, 2 (11%) ductal adenocarcinoma, and 1 (5%) mixed ductal and acinar adenocarcinoma. Conclusions At radical prostatectomy men in whom prior biopsies showed only intraductal carcinoma of the prostate typically have high grade (Gleason score 7 or greater) invasive adenocarcinoma and most have advanced stage disease (pT3). Definitive therapy is recommended in men with intraductal carcinoma of the prostate on needle biopsy even in the absence of pathologically documented invasive prostate cancer.
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.
Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on ...clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.
Background
A definitive diagnosis of prostate cancer requires a biopsy to obtain tissue for pathologic analysis, but this is an invasive procedure and is associated with complications.
Purpose
To ...develop an artificial intelligence (AI)‐based model (named AI‐biopsy) for the early diagnosis of prostate cancer using magnetic resonance (MR) images labeled with histopathology information.
Study Type
Retrospective.
Population
Magnetic resonance imaging (MRI) data sets from 400 patients with suspected prostate cancer and with histological data (228 acquired in‐house and 172 from external publicly available databases).
Field Strength/Sequence
1.5 to 3.0 Tesla, T2‐weighted image pulse sequences.
Assessment
MR images reviewed and selected by two radiologists (with 6 and 17 years of experience). The patient images were labeled with prostate biopsy including Gleason Score (6 to 10) or Grade Group (1 to 5) and reviewed by one pathologist (with 15 years of experience). Deep learning models were developed to distinguish 1) benign from cancerous tumor and 2) high‐risk tumor from low‐risk tumor.
Statistical Tests
To evaluate our models, we calculated negative predictive value, positive predictive value, specificity, sensitivity, and accuracy. We also calculated areas under the receiver operating characteristic (ROC) curves (AUCs) and Cohen's kappa.
Results
Our computational method (https://github.com/ih-lab/AI-biopsy) achieved AUCs of 0.89 (95% confidence interval CI: 0.86–0.92) and 0.78 (95% CI: 0.74–0.82) to classify cancer vs. benign and high‐ vs. low‐risk of prostate disease, respectively.
Data Conclusion
AI‐biopsy provided a data‐driven and reproducible way to assess cancer risk from MR images and a personalized strategy to potentially reduce the number of unnecessary biopsies. AI‐biopsy highlighted the regions of MR images that contained the predictive features the algorithm used for diagnosis using the class activation map method. It is a fully automatic method with a drag‐and‐drop web interface (https://ai-biopsy.eipm-research.org) that allows radiologists to review AI‐assessed MR images in real time.
Level of Evidence
1
Technical Efficacy Stage
2
Upper tract urothelial carcinoma (UTUC) is characterized by a distinctly aggressive clinical phenotype. To define the biological features driving this phenotype, we performed an integrated analysis ...of whole-exome and RNA sequencing of UTUC. Here we report several key insights from our molecular dissection of this disease: 1) Most UTUCs are luminal-papillary; 2) UTUC has a T-cell depleted immune contexture; 3) High FGFR3 expression is enriched in UTUC and correlates with its T-cell depleted immune microenvironment; 4) Sporadic UTUC is characterized by a lower total mutational burden than urothelial carcinoma of the bladder. Our findings lay the foundation for a deeper understanding of UTUC biology and provide a rationale for the development of UTUC-specific treatment strategies.
Mortality rates for maintenance hemodialysis patients are much higher than the general population and are even greater soon after starting dialysis. Here we analyzed mortality patterns in 86,886 ...patients in 11 countries focusing on the early dialysis period using data from the Dialysis Outcomes and Practice Patterns Study, a prospective cohort study of in-center hemodialysis. The primary outcome was all-cause mortality, using time-dependent Cox regression, stratified by study phase adjusted for age, sex, race, and diabetes. The main predictor was time since dialysis start as divided into early (up to 120 days), intermediate (121–365 days), and late (over 365 days) periods. Mortality rates (deaths/100 patient-years) were 26.7 (95% confidence intervals 25.6–27.9), 16.9 (16.2–17.6), and 13.7 (13.5–14.0) in the early, intermediate, and late periods, respectively. In each country, mortality was higher in the early compared to the intermediate period, with a range of adjusted mortality ratios from 3.10 (2.22–4.32) in Japan to 1.15 (0.87–1.53) in the United Kingdom. Adjusted mortality rates were similar for intermediate and late periods. The ratio of elevated mortality rates in the early to the intermediate period increased with age. Within each period, mortality was higher in the United States than in most other countries. Thus, internationally, the early hemodialysis period is a high-risk time for all countries studied, with substantial differences in mortality between countries. Efforts to improve outcomes should focus on the transition period and the first few months of dialysis.
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