Prostate epithelial genes define therapy-relevant prostate cancer molecular subtype

Abstract Background and objectives Transcriptomic landscape of prostate cancer (PCa) shows multidimensional variability, potentially arising from the cell-of-origin, reflected in serum markers, and most importantly related to drug sensitivities. For example, Aggressive Variant Prostate Cancer (AVPC) presents low PSA per tumor burden, and characterized by de novo resistance to androgen receptor signaling inhibitors (ARIs). Understanding PCa transcriptomic complexity can provide biological insight and therapeutic guidance. However, unsupervised clustering analysis is hindered by potential confounding factors such as stromal contamination and stress-related material degradation. Materials and methods To focus on prostate epithelial cell-relevant heterogeneity, we defined 1,629 genes expressed by prostate epithelial cells by analyzing publicly available bulk and single- cell RNA sequencing data. Consensus clustering and CIBERSORT deconvolution were used for class discovery and proportion estimate analysis. The Cancer Genome Atlas Prostate Adenocarcinoma dataset served as a training set. The resulting clusters were analyzed in association with clinical, pathologic, and genomic characteristics and impact on survival. Serum markers PSA and PAP was analyzed to predict response to docetaxel chemotherapy in metastatic setting. Results We identified two luminal subtypes and two aggressive variant subtypes of PCa: luminal A (Adipogenic/AR-active/PSA-high) (30.0%); luminal S (Secretory/PAP-high) (26.0%); AVPC-I (Immune-infiltrative) (14.7%), AVPC-M (Myc-active) (4.2%), and mixed (25.0%). AVPC-I and AVPC-M subtypes predicted to be resistant to ARI and have low PSA per tumor burden. Luminal A and AVPC-M predicted to be resistant to docetaxel and have high PSA/PAP Ratio. Metastatic PCa patients with high PSA/PAP ratio (>20) had significantly shorter progression-free survival than those with low ratio (≤20) following docetaxel chemotherapy. Conclusion We propose four prostate adenocarcinoma subtypes with distinct transcriptomic, genomic, and pathologic characteristics. PSA/PAP ratio in advanced cancer may aid in determining which patients would benefit from maximized androgen receptor inhibition or early use of antimicrotubule agents.

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Morphologic, Molecular and Clinical Features of Aggressive Variant Prostate Cancer

Cells ◽

10.3390/cells9051073 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1073 ◽

Cited By ~ 2

Author(s):

Rodolfo Montironi ◽

Alessia Cimadamore ◽

Antonio Lopez-Beltran ◽

Marina Scarpelli ◽

Gaetano Aurilio ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Large Cell Carcinoma ◽

Large Cell ◽

Final Diagnosis ◽

Undifferentiated Carcinoma ◽

Castration Resistant Prostate Cancer ◽

Platinum Based Chemotherapy ◽

Intermediate Part ◽

Aggressive Variant

The term aggressive variant prostate cancer (AVPCa) refers to androgen receptor (AR)-independent anaplastic forms of prostate cancer (PCa), clinically characterized by a rapidly progressive disease course. This involves hormone refractoriness and metastasis in visceral sites. Morphologically, AVPCa is made up of solid sheets of cells devoid of pleomorphism, with round and enlarged nuclei with prominent nucleoli and slightly basophilic cytoplasm. The cells do not show the typical architectural features of prostatic adenocarcinoma and mimic the undifferentiated carcinoma of other organs and locations. The final diagnosis is based on the immunohistochemical expression of markers usually seen in the prostate, such as prostate-specific membrane antigen (PSMA). A subset of AVPCa can also express neuroendocrine (NE) markers such as chromogranin A, synaptophysin and CD56. This letter subset represents an intermediate part of the spectrum of NE tumors which ranges from small cell to large cell carcinoma. All such tumors can develop following potent androgen receptor pathway inhibition. This means that castration-resistant prostate cancer (CRPCa) transdifferentiates and becomes a treatment-related NE PCa in a clonally divergent manner. The tumors that do not show NE differentiation might harbor somatic and/or germline alterations in the DNA repair pathway. The identification of these subtypes has direct clinical relevance with regard to the potential benefit of platinum-based chemotherapy, poly (ADP-ribose) polymerase inhibitors and likely further therapies.

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Current Status and Future Perspectives of Androgen Receptor Inhibition Therapy for Prostate Cancer: A Comprehensive Review

Biomolecules ◽

10.3390/biom11040492 ◽

2021 ◽

Vol 11 (4) ◽

pp. 492

Author(s):

Tae Jin Kim ◽

Young Hwa Lee ◽

Kyo Chul Koo

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Treatment Strategies ◽

Current Status ◽

Treatment Modalities ◽

Molecular Pathways ◽

Castration Resistant Prostate Cancer ◽

Novel Treatments ◽

Metastatic Setting ◽

Study Results

The androgen receptor (AR) is one of the main components in the development and progression of prostate cancer (PCa), and treatment strategies are mostly directed toward manipulation of the AR pathway. In the metastatic setting, androgen deprivation therapy (ADT) is the foundation of treatment in patients with hormone-sensitive prostate cancer (HSPC). However, treatment response is short-lived, and the majority of patients ultimately progress to castration-resistant prostate cancer (CRPC). Surmountable data from clinical trials have shown that the maintenance of AR signaling in the castration environment is accountable for disease progression. Study results indicate multiple factors and survival pathways involved in PCa. Based on these findings, the alternative molecular pathways involved in PCa progression can be manipulated to improve current regimens and develop novel treatment modalities in the management of CRPC. In this review, the interaction between AR signaling and other molecular pathways involved in tumor pathogenesis and its clinical implications in metastasis and advanced disease will be discussed, along with a thorough overview of current and ongoing novel treatments for AR signaling inhibition.

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Metastatic ductal carcinoma of the prostate: a rare variant responding to a common treatment

Canadian Urological Association Journal ◽

10.5489/cuaj.830 ◽

2013 ◽

Vol 4 (2) ◽

pp. 50 ◽

Cited By ~ 8

Author(s):

Aalok Kumar ◽

Som Dave Mukherjee

Keyword(s):

Prostate Cancer ◽

Overall Survival ◽

Rare Variant ◽

Prostate Carcinoma ◽

Poor Prognosis ◽

Ductal Carcinoma ◽

Prostate Adenocarcinoma ◽

Histologic Subtype ◽

Carcinoma Of The Prostate ◽

Docetaxel Chemotherapy

Ductal carcinoma of the prostate is a rare histologic subtype ofprostate carcinoma. It represents 0.4% to 0.8% of all prostatecancers and is associated with a poor prognosis. Given the paucityof cases reported in the literature on ductal prostate carcinoma,little is known about how this cancer responds to cytotoxicchemotherapy. We report the case of a 56-year-old male whopresented to our clinic with hemoptysis, cough and hematuriaand was found to have metastatic ductal carcinoma of the prostate.He was initiated on docetaxel chemotherapy, which has beenpreviously shown to improve overall survival in patients withmetastatic prostate adenocarcinoma, but has never been studiedin this less common subtype of prostate cancer. To the best ofour knowledge, the following is the first reported case of a patientwith metastatic ductal carcinoma of the prostate responding todocetaxel chemotherapy.

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Prostate Epithelial Genes Define Docetaxel-Sensitive Prostate Cancer Molecular Subtype

10.1101/2020.08.26.269415 ◽

2020 ◽

Author(s):

Hyunho Han ◽

Kwibok Choi ◽

Young Jun Moon ◽

Ji Eun Heo ◽

Won Sik Ham ◽

...

Keyword(s):

Prostate Cancer ◽

Epithelial Cells ◽

Single Cell ◽

Molecular Subtype ◽

Prostate Gland ◽

Specific Antigen ◽

Prostate Adenocarcinoma ◽

The Cancer Genome Atlas ◽

Subtype B ◽

Prostate Epithelial Cells

ABSTRACTBACKGROUND & OBJECTIVESAnalysis of the transcriptomic landscape of prostate adenocarcinoma shows multidimensional gene expression variability. Understanding cancer transcriptome complexity can provide biological insight and therapeutic guidance. To avoid potential confounding factors, such as stromal contamination and stress-related material degradation, we utilized a set of genes expressed by prostate epithelial cells from single-cell transcriptome data of the human prostate gland.MATERIALS & METHODSAnalyzing publicly available bulk and single-cell RNA sequencing data, we defined 1,629 genes expressed by prostate epithelial cells. Consensus clustering and CIBERSORT deconvolution were used for class discovery and proportion estimate analysis. The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) dataset served as a training set. The resulting clusters were analyzed in association with clinical, pathologic, and genomic characteristics and impact on survival.RESULTSTCGA-PRAD tumors were separated into four subtypes: A (30.0%), B (26.0%), C (14.7%), D (4.2%), and mixed (25.0%). Subtype A was characterized by low frequency of ETS-family fusions and high expression of KLK3, which encodes prostate-specific antigen (PSA). Subtype B showed the highest expression of ACP3, encoding PAP (prostatic acid phosphatase). Subtypes C and D were commonly associated with advanced T/N stages, high Gleason grades, and p53 or PIK3CA mutations. In silico drug-sensitivity screening suggested that subtype B is likely sensitive to docetaxel and paclitaxel. Serum PSA/PAP ratio was predictive of a radiographic response to docetaxel in metastatic castration-resistant prostate cancer patients.CONCLUSIONWe propose four prostate adenocarcinoma subtypes with distinct transcriptomic, genomic, and pathologic characteristics. PSA/PAP ratio in advanced cancer may aid in determining which patients would benefit from maximized androgen receptor inhibition or early use of antimicrotubule agents. Molecular subtypes and biomarkers must be validated in a prospective cohort study.

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Oncogenic Role of Secreted Engrailed Homeobox 2 (EN2) in Prostate Cancer

Journal of Clinical Medicine ◽

10.3390/jcm8091400 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1400 ◽

Cited By ~ 5

Author(s):

Gómez-Gómez E. ◽

Jiménez-Vacas J. M. ◽

Pedraza-Arévalo S. ◽

López-López F. ◽

Herrero-Aguayo V. ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Functional Role ◽

The Cancer Genome Atlas ◽

Cancer Center ◽

Diagnostic Biomarker ◽

Lncap Cells ◽

Prostate Cells ◽

Pc3 Cells

Engrailed variant-2 (EN2) has been suggested as a potential diagnostic biomarker; however, its presence and functional role in prostate cancer (PCa) cells is still controversial or unknown. Here, we analyzed 1) the expression/secretion profile of EN2 in five independent samples cohorts from PCa patients and controls (prostate tissues and/or urine) to determine its utility as a PCa biomarker; and 2) the functional role of EN2 in normal (RWPE1) and tumor (LNCaP/22Rv1/PC3) prostate cells to explore its potential value as therapeutic target. EN2 was overexpressed in our two cohorts of PCa tissues compared to control and in tumor cell lines compared with normal-like prostate cells. This profile was corroborated in silico in three independent data sets [The Cancer Genome Atlas(TCGA)/Memorial Sloan Kettering Cancer Center (MSKCC)/Grasso]. Consistently, urine EN2 levels were elevated and enabled discrimination between PCa and control patients. EN2 treatment increased cell proliferation in LNCaP/22Rv1/PC3 cells, migration in RWPE1/PC3 cells, and PSA secretion in LNCaP cells. These effects were associated, at least in the androgen-sensitive LNCaP cells, with increased AKT and androgen-receptor phosphorylation levels and with modulation of key cancer-associated genes. Consistently, EN2 treatment also regulated androgen-receptor activity (full-length and splicing variants) in androgen-sensitive 22Rv1 cells. Altogether, this study demonstrates the potential utility of EN2 as a non-invasive diagnostic biomarker for PCa and provides novel and valuable information to further investigate its putative utility to develop new therapeutic tools in PCa.

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A Novel Model Based on Necroptosis-Related Genes for Predicting Prognosis of Patients With Prostate Adenocarcinoma

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.814813 ◽

2022 ◽

Vol 9 ◽

Author(s):

Xin-yu Li ◽

Jian-xiong You ◽

Lu-yu Zhang ◽

Li-xin Su ◽

Xi-tao Yang

Keyword(s):

Prostate Cancer ◽

Prognostic Model ◽

Clinical Information ◽

Roc Curves ◽

Prostate Adenocarcinoma ◽

The Cancer Genome Atlas ◽

Good Prediction ◽

Bioinformatics Analyses ◽

High Risk Prostate Cancer ◽

Good Prediction Accuracy

Background: Necroptosis is a newly recognized form of cell death. Here, we applied bioinformatics tools to identify necroptosis-related genes using a dataset from The Cancer Genome Atlas (TCGA) database, then constructed a model for prognosis of patients with prostate cancer.Methods: RNA sequence (RNA‐seq) data and clinical information for Prostate adenocarcinoma (PRAD) patients were obtained from the TCGA portal (http://tcga-data.nci.nih.gov/tcga/). We performed comprehensive bioinformatics analyses to identify hub genes as potential prognostic biomarkers in PRAD u followed by establishment and validation of a prognostic model. Next, we assessed the overall prediction performance of the model using receiver operating characteristic (ROC) curves and the area under curve (AUC) of the ROC.Results: A total of 5 necroptosis-related genes, namely ALOX15, BCL2, IFNA1, PYGL and TLR3, were used to construct a survival prognostic model. The model exhibited excellent performance in the TCGA cohort and validation group and had good prediction accuracy in screening out high-risk prostate cancer patients.Conclusion: We successfully identified necroptosis-related genes and constructed a prognostic model that can accurately predict 1- 3-and 5-years overall survival (OS) rates of PRAD patients. Our riskscore model has provided novel strategy for the prediction of PRAD patients’ prognosis.

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Abstract 923: Analysis of microtubule perturbations and androgen receptor localization in circulating tumor cells from castration resistant prostate cancer patients as predictive biomarkers of clinical response to docetaxel chemotherapy

10.1158/1538-7445.am2014-923 ◽

2014 ◽

Author(s):

Shinsuke Tasaki ◽

Matthew Sung ◽

Alexandre Matov ◽

Giuseppe Galletti ◽

Elan Diamond ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Clinical Response ◽

Cancer Patients ◽

Tumor Cells ◽

Predictive Biomarkers ◽

Castration Resistant Prostate Cancer ◽

Receptor Localization ◽

Castration Resistant ◽

Docetaxel Chemotherapy

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The Identification of Critical m6A RNA Methylation Regulators as Malignant Prognosis Factors in Prostate Adenocarcinoma

Frontiers in Genetics ◽

10.3389/fgene.2020.602485 ◽

2020 ◽

Vol 11 ◽

Author(s):

Jiaju Xu ◽

Yuenan Liu ◽

Jingchong Liu ◽

Tianbo Xu ◽

Gong Cheng ◽

...

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Cox Regression ◽

Enrichment Analysis ◽

Prostate Adenocarcinoma ◽

The Cancer Genome Atlas ◽

Functional Enrichment ◽

Consensus Clustering ◽

Human Beings ◽

Rna Methylation

RNA methylation accounts for over 60% of all RNA modifications, and N6-methyladenosine (m6A) is the most common modification on mRNA and lncRNA of human beings. It has been found that m6A modification occurs in microRNA, circRNA, rRNA, and tRNA, etc. The m6A modification plays an important role in regulating gene expression, and the abnormality of its regulatory mechanism refers to many human diseases, including cancers. Pitifully, as it stands there is a serious lack of knowledge of the extent to which the expression and function of m6A RNA methylation can influence prostate cancer (PC). Herein, we systematically analyzed the expression levels of 35 m6A RNA methylation regulators mentioned in literatures among prostate adenocarcinoma patients in the Cancer Genome Atlas (TCGA), finding that most of them expressed differently between cancer tissues and normal tissues with the significance of p < 0.05. Utilizing consensus clustering, we divided PC patients into two subgroups based on the differentially expressed m6A RNA methylation regulators with significantly different clinical outcomes. To appraise the discrepancy in total transcriptome between subgroups, the functional enrichment analysis was conducted for differential signaling pathways and cellular processes. Next, we selected five critical genes by the criteria that the regulators had a significant impact on prognosis of PC patients from TCGA through the last absolute shrinkage and selection operator (LASSO) Cox regression and obtained a risk score by weighted summation for prognosis prediction. The survival analysis curve and receiver operating characteristic (ROC) curve showed that this signature could excellently predict the prognosis of PC patients. The univariate and multivariate Cox regression analyses proved the independent prognostic value of the signature. In summary, our effort revealed the significance of m6A RNA methylation regulators in prostate cancer and determined a m6A gene expression classifier that well predicted the prognosis of prostate cancer.

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