scholarly journals Identification of Key Gene Signatures Associated With Bone Metastasis in Castration-Resistant Prostate Cancer Using Co-Expression Analysis

2021 ◽  
Vol 10 ◽  
Author(s):  
Zhongxiang Yu ◽  
Hanlin Zou ◽  
Huihao Wang ◽  
Qi Li ◽  
Dong Yu
Keyword(s):  
Prostate Cancer ◽  
Bone Marrow ◽  
Bone Metastasis ◽  
Molecular Mechanisms ◽  
Bone Development ◽  
Tumor Development ◽  
Enrichment Analysis ◽  
Castration Resistant Prostate Cancer ◽  
Metastatic Colonization ◽  
Castration Resistant

About 80–90% of castration-resistant prostate cancer (CRPC) patients would develop bone metastasis. However, the molecular mechanisms of bone metastasis are still not clear. This study aimed to detect the differences between the tumor and normal samples in bone after metastatic colonization. Four transcriptional datasets (GSE32269, GSE101607, GSE29650, and GSE74685) were obtained from the GEO database. 1983 differentially expressed genes (DEGs) were first identified between tumor and normal marrow samples in GSE32269. Most of the top 10 up-regulated DEGs are related with prostate cancer, and the top 10 down-regulated DEGs are mainly related with bone development. Seven co-expression modules were then detected based on the 1469 DEGs shared by the four datasets. Three of them were found highly preserved among the four datasets. Enrichment analysis showed that the three modules were respectively enriched in Cell adhesion molecules (CAMs), Leukocyte transendothelial migration and cell cycle, which might play significantly important roles in the tumor development in bone marrow. Ten, 17, and 99 hub genes for each module were then identified. And four genes (C3AR1, IL10RA, LY86, and MS4A6A) were detect to be tightly related to progression of bone metastatic CRPC. ROC curve was plotted and AUC was calculated to distinguish tumor and normal bone marrow samples as well as bone and non-bone metastatic CRPCs. The present study identified key genes and modules involved in bone metastatic CRPCs, which may provide new insights and biomarkers for understanding of the molecular mechanisms of bone metastatic CRPC.

scholarly journals Candidate biomarkers and gene modules investigation for bone tumor samples derived from castration-resistant prostate cancer bone metastasis patients using WGCNA

2019 ◽  
Author(s):  
Zhongxiang Yu ◽  
Hanlin Zou ◽  
Huihao Wang ◽  
Qi Li ◽  
Dong Yu
Keyword(s):  
Prostate Cancer ◽  
Bone Marrow ◽  
Bone Metastasis ◽  
Bone Tumor ◽  
Castration Resistant Prostate Cancer ◽  
Hub Genes ◽  
Chemotherapy Drugs ◽  
Castration Resistant ◽  
Bone Targeting ◽  
Radium 223

Abstract Background About 80-90% of castration-resistant prostate cancer (CRPC) patients would develop bone metastasis, which leads to the disorder of bone metabolism and induces skeletal related events. However, except for the few approved radiotherapeutic and chemotherapy drugs, like radium-223 and denosumab, there is still lack of effective treatment targeting the bone metastatic tumor. It is necessary and significant to explore the mechanisms of bone metastasis and tumorigenesis, especially the differences between the tumor and normal cells in bone after metastatic colonization, which will provide a set of candidate genes for the screening of novel bone targeting agents.Results 4 datasets (GSE32269, GSE101607, GSE29650 and GSE74685) were obtained from the GEO database. 1983 differentially expressed genes (DEGs) were first identified between bone marrow tumor samples and normal marrow samples in GSE32269, followed by the weighted gene co-expression analysis. Most of the top 10 DEGs are found to be related with prostate cancer. 7 co-expression modules were then detected based on the 1469 DEGs shared by the 4 datasets, and 3 of them were found highly preserved among the other three datasets. The top 30 hub genes of the 3 modules were extracted. Among the enriched pathways of preserved modules, Cell adhesion molecules (CAMs) and Leukocyte transendothelial migration might play significant important roles in the tumor development in bone marrow. Literature searches further showed that a set of DEGs and hub genes might also contribute to the development of tumor in bone.Conclusions Together, our findings not only provide outline of expression profile in CRPC bone metastasis, but also screen a set of genes associated with CPRC tumor cell colonization and development of bone tumor, which could be helpful for novel bone targeting agents screening.

Evaluation of bone metastasis of castration-resistant prostate cancer after enzalutamide and abiraterone using Bone Scan Index on bone scintigraphy.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. e596-e596
Author(s):  
Suguru Kadomoto ◽  
Kouji Izumi ◽  
Takahiro Nohara ◽  
Konaka Hiroyuki ◽  
Yoshifumi Kadono ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Bone Scintigraphy ◽  
Bone Scan ◽  
Average Rate ◽  
Castration Resistant Prostate Cancer ◽  
Bone Scan Index ◽  
Castration Resistant ◽  
Better Than

e596 Background: It was ambiguous till now to evaluate the change of bone metastasis by various treatments. To quantify the change of bone metastases by enzalutamide, abiraterone, and docetaxel for the castration-resistant prostate cancer (CRPC) with bone metastases (bmCRPC), we employed Bone Scan Index (BSI) on bone scintigraphy. Methods: We retrospectively evaluated the change of PSA and bone metastases of CRPC patients who were treated with enzalutamide (Enz), abiraterone (Abi) and/or docetaxel (DOC) in our hospital. All patients underwent Tc-99m MDP bone scintigraphy. The degree of bone metastases was analyzed using BSI, which was calculated by BONENAVI (FUJIFILM RI Pharma, Japan; EXINIbone, EXINI Diagnostics, Sweden). 19 patients were treated with enzalutamide (8 cases: pre-docetaxel, 11 cases: post-docetaxel). The median PSA of patients treated with Enz was 12.64 ng/ml (1.63-199 ng/ml). And 11 patients were treated with abiraterone (5 cases: pre-docetaxel, 6 cases: post-docetaxel). The median PSA of patients treated with Abi was 26.37 ng/ml (2.29-199 ng/ml). Results: We observed decline of PSA in 18/30 cases (9 cases: pre-DOC, 9 cases: post-DOC). Decline of PSA to 50% or more was observed in 14 cases. In contrast, decline of BSI was observed in 53.3% (16/30) cases and decline of PSA to 25% or more was observed in only 6 cases. BSI decreased in 84.6% (11/13) of pre-DOC setting and in 29.4% (5/17) of post-DOC setting indicating that change of BSI was poor in post-DOC setting. However, DOC had already decreased BSI in 91.7% (11/12) before Abi or Enz treatment. Moreover, the average rate of BSI decline in the patients that BSI decreased by DOC was better than the patients that BSI decreased by Abi/Enz (-48.46% vs -28.56%). Finally, although the rate of BSI change by Enz was weakly correlated with the rate of PSA decline (y = 0.3906x + 25.35, R2 = 0.3423), BSI continued to increase in four cases in spite of PSA decline. Conclusions: BSI using BONENAVI on bone scintigraphy was helpful for evaluating the effectiveness of treatment and following-up of bmCRPC.

Genomic drivers of poor prognosis and enzalutamide resistance in metastatic castration-resistant prostate cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 146-146
Author(s):  
William S. Chen ◽  
Rahul Raj Aggarwal ◽  
Li Zhang ◽  
Shuang Zhao ◽  
Tomasz M. Beer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Beta Catenin ◽  
Rna Seq ◽  
Castration Resistant Prostate Cancer ◽  
Gene Set Enrichment ◽  
Poor Overall Survival ◽  
Castration Resistant

146 Background: Metastatic castration-resistant prostate cancer (mCRPC) is the lethal form of the disease. Several recent efforts have identified genomic alterations in mCRPC, but the clinical implications of these alterations have not been fully elucidated. We conducted a prospective cohort study (n = 101) using whole genome sequencing (WGS) to analyze the association between key driver gene alterations and overall survival. We also performed whole-transcriptome RNA sequencing (RNA-seq) analyses to identify potential mechanisms of enzalutamide resistance in mCRPC. Methods: Metastasis biopsies were obtained in 101 mCRPC patients as part of the multi-institutional West Coast Prostate Cancer Dream Team project. Samples underwent WGS and RNA-seq. The resulting mutation, copy number, and structural variant calls were integrated to determine functional copy number status of candidate genes for downstream clinical analyses. We performed univariate and multivariable analyses to assess the prognostic significance of candidate genomic events with respect to overall survival. To nominate and investigate genomic pathways associated with enzalutamide resistance, we performed expression-based gene set enrichment analysis followed by cross-sectional enrichment and survival analyses related to the top nominated pathway. Results: RB1 loss was associated with poor overall survival (median 14.1 vs. 42.0 months, p < 0.001). When we compared enzalutamide resistant versus naïve samples using gene set enrichment analysis, we identified the Wnt/beta-catenin pathway as the top differentially expressed pathway in enzalutamide-resistant patients. Furthermore, CTNNB1 (beta-catenin) activating mutations were exclusive to enzalutamide-resistant patients (p = 0.013) and predictive of poor overall survival (median 13.6 vs. 41.7 months, p < 0.001). Conclusions: Impaired survival in mCRPC patients is associated with RB1 loss, identified by integrated genomic analysis of CRPC metastasis biopsies. Among men with mCRPC that was enzalutamide-resistant, the Wnt/beta-catenin pathway is nominated as an important predictive (and potentially therapeutic) pathway.

Evaluation of Docetaxel-Sensitive and Docetaxel-Resistant Proteomes in PC-3 Cells

2015 ◽  
Vol 95 (1) ◽  
pp. 114-119 ◽  
Author(s):  
Shulu Zu ◽  
Weiming Ma ◽  
Pan Xiao ◽  
Yazhou Cui ◽  
Tianjia Ma ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Molecular Mechanisms ◽  
Polyacrylamide Gel Electrophoresis ◽  
Acquired Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Ionization Time ◽  
Flight Mass Spectrometry ◽  
Docetaxel Resistance ◽  
Castration Resistant ◽  
Glucose Regulated Protein

Objectives: Docetaxel was the first drug with proven survival benefit in men with castration-resistant prostate cancer. Acquired resistance to docetaxel precedes fatality in castration-resistant prostate cancer. The aims of this study were to evaluate docetaxel-sensitive and docetaxel-resistant proteomes in PC-3 cells, and to investigate the molecular mechanism of docetaxel-resistant PC-3 cells. Methods: Docetaxel-resistant PC-3 cells were developed by docetaxel dose escalation. The global profiling of the protein expression was investigated in docetaxel-sensitive and docetaxel-resistant proteomes in PC-3 cells using 2-dimensional polyacrylamide gel electrophoresis/matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Results: Forty-nine differential proteins were found in docetaxel-resistant PC-3 cells in comparison with docetaxel-sensitive PC-3 cells. Expression in 29 proteins was upregulated, whereas expression in 20 proteins was downregulated. ATP synthase and galectin-1 were involved in the formation of tumor vessels; calreticulin, cathepsin D, and cofilin were involved in tumor metastasis, and GRP78 (78-kDa glucose-regulated protein) and microtubule-associated protein-6 were involved in drug resistance of tumor. Conclusion: It is suggested that a proteomic expression difference exists between docetaxel-sensitive and docetaxel-resistant PC-3 cells, which would be helpful for further understanding the molecular mechanisms of docetaxel resistance in PC-3 cells.

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