Genetic Analysis Reveals a Significant Contribution of CES1 to Prostate Cancer Progression in Taiwanese Men

The genes that influence prostate cancer progression remain largely unknown. Since the carboxylesterase gene family plays a crucial role in xenobiotic metabolism and lipid/cholesterol homeostasis, we hypothesize that genetic variants in carboxylesterase genes may influence clinical outcomes for prostate cancer patients. A total of 478 (36 genotyped and 442 imputed) single nucleotide polymorphisms (SNPs) in five genes of the carboxylesterase family were assessed in terms of their associations with biochemical recurrence (BCR)-free survival in 643 Taiwanese patients with prostate cancer who underwent radical prostatectomy. The strongest association signal was shown in CES1 (P = 9.64 × 10−4 for genotyped SNP rs8192935 and P = 8.96 × 10−5 for imputed SNP rs8192950). After multiple test correction and adjustment for clinical covariates, CES1 rs8192935 (P = 9.67 × 10−4) and rs8192950 (P = 9.34 × 10−5) remained significant. These SNPs were correlated with CES1 expression levels, which in turn were associated with prostate cancer aggressiveness. Furthermore, our meta-analysis, including eight studies, indicated that a high CES1 expression predicted better outcomes among prostate cancer patients (hazard ratio 0.82, 95% confidence interval 0.70–0.97, P = 0.02). In conclusion, our findings suggest that CES1 rs8192935 and rs8192950 are associated with BCR and that CES1 plays a tumor suppressive role in prostate cancer.

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Reliability of Serial Prostate Magnetic Resonance Imaging to Detect Prostate Cancer Progression During Active Surveillance: A Systematic Review and Meta-analysis

European Urology ◽

10.1016/j.eururo.2021.05.001 ◽

2021 ◽

Author(s):

Pawel Rajwa ◽

Benjamin Pradere ◽

Fahad Quhal ◽

Keiichiro Mori ◽

Ekaterina Laukhtina ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Prostate Cancer ◽

Systematic Review ◽

Magnetic Resonance ◽

Active Surveillance ◽

Cancer Progression ◽

Meta Analysis ◽

Prostate Cancer Progression ◽

Resonance Imaging ◽

Detect Prostate Cancer

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Embigin Promotes Prostate Cancer Progression by S100A4-Dependent and-Independent Mechanisms

Cancers ◽

10.3390/cancers10070239 ◽

2018 ◽

Vol 10 (7) ◽

pp. 239 ◽

Cited By ~ 3

Author(s):

I Ruma ◽

Rie Kinoshita ◽

Nahoko Tomonobu ◽

Yusuke Inoue ◽

Eisaku Kondo ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Cancer Progression ◽

Immunoglobulin Superfamily ◽

Prostate Cancer Progression ◽

Transmembrane Glycoprotein ◽

Mtorc1 Signaling ◽

Ampk Activity ◽

In Vivo Growth

Embigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is involved in prostate and mammary gland development. As embigin’s roles in cancer remain elusive, we studied its biological functions and interaction with extracellular S100A4 in prostate cancer progression. We found by a pull-down assay that embigin is a novel receptor for S100A4, which is one of the vital cancer microenvironment milleu. Binding of extracellular S100A4 to embigin mediates prostate cancer progression by inhibition of AMPK activity, activation of NF-κB, MMP9 and mTORC1 signaling, and inhibition of autophagy, which increase prostate cancer cell motility. We also found that embigin promotes prostate cancer growth, spheroid- and colony-forming ability, and survival upon chemotherapy independently of S100A4. An in vivo growth mouse model confirmed the importance of embigin and its cytoplasmic tail in mediating prostate tumor growth. Moreover, embigin and p21WAF1 can be used to predict survival of prostate cancer patients. Our results demonstrated for the first time that the S100A4-embigin/AMPK/mTORC1/p21WAF1 and NF-κB/MMP9 axis is a vital oncogenic molecular cascade for prostate cancer progression. We proposed that embigin and p21WAF1 could be used as prognostic biomarkers and a strategy to inhibit S100A4-embigin binding could be a therapeutic approach for prostate cancer patients.

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Abstract 3448: ERG-negative index tumor status combined with obesity predict prostate cancer progression in Caucasian American prostate cancer patients

10.1158/1538-7445.am2016-3448 ◽

2016 ◽

Author(s):

Jennifer Cullen ◽

Denise Young ◽

Yongmei Chen ◽

Michael S. Degon ◽

Wagner Baptiste ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Cancer Progression ◽

Negative Index ◽

Prostate Cancer Progression ◽

Caucasian American ◽

Index Tumor

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Variation in UDP glucouronyltransferase (UGT) genes associated with prostate cancer mortality.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.7_suppl.44 ◽

2011 ◽

Vol 29 (7_suppl) ◽

pp. 44-44

Author(s):

M. Kohli ◽

D. W. Mahoney ◽

H. S. Chai ◽

D. W. Hillman ◽

D. R. Rider ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Cancer Progression ◽

Advanced Prostate Cancer ◽

Cox Regression ◽

Prostate Cancer Progression ◽

Androgen Ablation ◽

Principle Components Analysis ◽

Specific Mortality ◽

Cancer Specific Mortality

44 Background: We investigated the association of germline genetic variation in hormone biosynthesis and metabolism genes with prostate cancer specific mortality in a cohort of advanced prostate cancer patients. Methods: We successfully genotyped 852 single nucleotide polymorphisms (SNPs) from 97 genes in a cohort of 267 advanced prostate cancer patients at the time of progression to castration recurrence (CRPC) during on-going androgen ablation. Tagging SNPs with minor allele frequency (MAF) of >5% and r2 ≥0.8 were selected from HapMap, NIEHS and Seattle SNP databases. Medical records were queried for cause of death. The primary endpoint of time to prostate cancer specific mortality (PCSM), was pre-defined as time from development of CRPC to death from prostate cancer progression. Principle components analysis was used for gene-levels tests, and to account for multiple testing, we calculated the false discovery rate (FDR). For SNP level results, hazard ratios (HR) and 95% confidence intervals (CI) were estimated using cox regression. Results: The median age of the cohort was 72 years at CRPC. 43% had a Gleason score (GS)=8-10, 33% a GS=7, and 24% a GS<7. After a median follow-up of 1.8 years (IQ range: 0.8–3.3 years), 139 patients died, of which 107 were due to prostate cancer progression. In unadjusted gene level analyses, UGT1A7 (p=0.0059; FDR=0.19), UGT1A10 (p=0.0017; FDR=0.17) and UGT1A3 (p=0.0037; FDR=0.18) were associated with PCSM. After adjusting for age and GS, SNPs strongly associated with PCSM are listed in the Table . Conclusions: Variation in UGT genes involved in hormone metabolism yield prognostic information in CRPC. Further validation is needed to develop these as prognostic biomarkers. [Table: see text] No significant financial relationships to disclose.

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Alterations in chromosome spatial compartmentalization classify prostate cancer progression

10.1101/2021.04.15.440056 ◽

2021 ◽

Author(s):

Rebeca San Martin ◽

Priyojit Das ◽

Renata Dos Reis Marques ◽

Yang Xu ◽

Rachel Patton McCord

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

3D Structure ◽

Gene Clusters ◽

Metastatic Potential ◽

Chromosome 21 ◽

Prostate Cancer Progression ◽

Normal Epithelium ◽

Chromosome Conformation ◽

Cancer Aggressiveness

Prostate cancer aggressiveness and metastatic potential are influenced by gene expression, genomic aberrations, and cellular morphology. These processes are in turn dependent in part on the 3D structure of chromosomes, packaged inside the nucleus. Using chromosome conformation capture (Hi-C), we conducted a systematic genome architecture comparison on a cohort of cell lines that model prostate cancer progression, ranging from normal epithelium to bone metastasis. Here, we describe how chromatin compartmentalization identity (A- open vs. B-closed) changes with progression: specifically, we find that 48 gene clusters switch from the B to the A compartment, including androgen receptor, WNT5A, and CDK14. These switches could prelude transcription activation and are accompanied by changes in the structure, size, and boundaries of the topologically associating domains (TADs). Further, compartmentalization changes in chromosome 21 are exacerbated with progression and may explain, in part, the genesis of the TMPRSS2-ERG translocation: one of the main drivers of prostate cancer.  These results suggest that discrete, 3D genome structure changes play a deleterious role in prostate cancer progression. 

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Linking obesogenic dysregulation to prostate cancer progression

Endocrine Connections ◽

10.1530/ec-15-0080 ◽

2015 ◽

Vol 4 (4) ◽

pp. R68-R80 ◽

Cited By ~ 16

Author(s):

Renea A Taylor ◽

Jennifer Lo ◽

Natasha Ascui ◽

Matthew J Watt

Keyword(s):

Prostate Cancer ◽

Adipose Tissue ◽

Cancer Progression ◽

Prostate Gland ◽

The Body ◽

Endocrine Function ◽

Low Grade ◽

Prostate Cancer Progression ◽

Cancer Aggressiveness ◽

Increased Risk

The global epidemic of obesity is closely linked to the development of serious co-morbidities, including many forms of cancer. Epidemiological evidence consistently shows that obesity is associated with a similar or mildly increased incidence of prostate cancer but, more prominently, an increased risk for aggressive prostate cancer and prostate cancer-specific mortality. Studies in mice demonstrate that obesity induced by high-fat feeding increases prostate cancer progression; however, the mechanisms underpinning this relationship remain incompletely understood. Adipose tissue expansion in obesity leads to local tissue dysfunction and is associated with low-grade inflammation, alterations in endocrine function and changes in lipolysis that result in increased delivery of fatty acids to tissues of the body. The human prostate gland is covered anteriorly by the prominent peri-prostatic adipose tissue and laterally by smaller adipose tissue depots that lie directly adjacent to the prostatic surface. We discuss how the close association between dysfunctional adipose tissue and prostate epithelial cells might result in bi-directional communication to cause increased prostate cancer aggressiveness and progression. However, the literature indicates that several ‘mainstream’ hypotheses regarding obesity-related drivers of prostate cancer progression are not yet supported by a solid evidence base and, in particular, are not supported by experiments using human tissue. Understanding the links between obesity and prostate cancer will have major implications for the health policy for men with prostate cancer and the development of new therapeutic or preventative strategies.

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Prognostic Value of CD1B in Localised Prostate Cancer

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16234723 ◽

2019 ◽

Vol 16 (23) ◽

pp. 4723 ◽

Cited By ~ 1

Author(s):

Cheng-Hsueh Lee ◽

Lih-Chyang Chen ◽

Chia-Cheng Yu ◽

Wen-Hsin Lin ◽

Victor C. Lin ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Cell Types ◽

Regulatory Elements ◽

Marker Genes ◽

Nucleotide Polymorphisms ◽

Prostate Cancer Progression ◽

Transcriptional Regulatory Elements ◽

Haematopoietic Cell ◽

The Impact

Cluster of differentiation (CD) antigens are cell surface markers used to differentiate haematopoietic cell types. These antigens are present in various malignancies and are reportedly linked to patient prognosis; however, they have not been implemented as prostate cancer progression markers. Here, we aimed to assess the impact of genetic variation in haematopoietic cell CD markers on clinical outcomes in patients with prostate cancer. An association study of 458 patients with prostate cancer was conducted to identify single-nucleotide polymorphisms in 11 candidate CD marker genes associated with biochemical recurrence (BCR) after radical prostatectomy. Identified predictors were further evaluated in an additional cohort of 185 patients. Joint population analyses showed that CD1B rs3181082 is associated with BCR (adjusted hazard ratio 1.42, 95% confidence interval 1.09–1.85, p = 0.010). In addition, rs3181082 overlapped with predicted transcriptional regulatory elements and affected CD1B expression. Furthermore, low CD1B expression correlated with poorer BCR-free survival. Our results indicated that CD1B rs3181082 confers prostate cancer progression and may help improve clinical prognostic stratification.

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Promoter Methylation in APC, RUNX3, and GSTP1 and Mortality in Prostate Cancer Patients

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.2485 ◽

2009 ◽

Vol 27 (19) ◽

pp. 3161-3168 ◽

Cited By ~ 99

Author(s):

Lorenzo Richiardi ◽

Valentina Fiano ◽

Loredana Vizzini ◽

Laura De Marco ◽

Luisa Delsedime ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Cancer Progression ◽

Promoter Methylation ◽

A Priori ◽

Methylation Status ◽

Specific Antigen ◽

Prostate Cancer Progression ◽

Increased Risk ◽

In The Beginning

Purpose There is a need to better understand prostate cancer progression and identify new prognostic markers for this tumor. We investigated the association between promoter methylation in a priori selected genes and survival in two independent large series of prostate cancer patients. Methods We followed up with two cohorts of patients (216 patients diagnosed in 1982 to 1988 and 243 patients diagnosed in 1993 to 1996) diagnosed at one hospital pathology ward in Turin, Italy. DNA was obtained from paraffin-embedded tumor tissues and evaluated for promoter methylation status in glutathione S-transferase (GSTP1), adenomatous polyposis coli (APC), and runt-related transcription factor 3 (RUNX3). Results The two cohorts had different prevalences of methylation in APC (P = .047), GSTP1 (P = .002), and RUNX3 (P < .001). Methylation in APC was associated with an increased risk of prostate cancer–specific mortality (hazard ratio [HR] = 1.42; 95% CI, 0.98 to 2.07 in the 1980s cohort; HR = 1.57; 95% CI, 0.95 to 2.62 in the 1990s cohort; HR = 1.49; 95% CI, 1.11 to 2.00 in the two cohorts combined). In subgroup analyses, the HRs were higher among patients with a Gleason score less than 8 (HR = 1.52; 95% CI, 0.85 to 2.73 in the 1980s cohort; HR = 2.09; 95% CI, 1.02 to 4.28 in the 1990s cohort). Methylation in RUNX3 was associated with prostate cancer mortality only in the 1990s cohort, and methylation in GSTP1 did not predict mortality in either cohort. Conclusion The pattern of hypermethylation may have changed after the introduction of prostate-specific antigen testing in the beginning of the 1990s. Promoter methylation in APC was identified as a marker for prostate cancer progression.

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CD117/c-kit Defines a Prostate CSC-Like Subpopulation Driving Progression and TKI Resistance

10.1101/256107 ◽

2018 ◽

Cited By ~ 1

Author(s):

Koran S. Harris ◽

Lihong Shi ◽

Brittni M. Foster ◽

Mary E. Mobley ◽

Phyllis L. Elliott ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Cancer Progression ◽

Kinase Inhibitors ◽

Marker Gene ◽

Dependent Manner ◽

Tumor Initiation ◽

Cancer Aggressiveness ◽

Tki Resistance ◽

And Migration

ABSTRACTCancer stem-like cells (CSCs) are associated with cancer progression, metastasis, and recurrence, and may also represent a subset of circulating tumor cells (CTCs). In our prior study, CTCs in advanced prostate cancer patients were found to express CD117/c-kit in a liquid biopsy. Whether CD117 expression played an active or passive role in the aggressiveness and migration of these CTCs remained an open question. In this study, we show that CD117 expression in prostate cancer patients is associated with decreased overall and progression-free survival and that activation and phosphorylation of CD117 increases in prostate cancer patients with higher Gleason grades. To determine how CD117 expression and activation by its ligand stem cell factor (SCF, kit ligand, steel factor) alter prostate cancer aggressiveness, we used LNCaP-C4-2 and PC3-mm human prostate cancer cells, which contain a CD117+ subpopulation. We demonstrate that CD117+ cells display increased proliferation and migration. In prostaspheres, CD117 expression enhances sphere formation. In both 2D and 3D cultures, stemness marker gene expression is higher in CD117+ cells. Using xenograft limiting dilution assays and serial tumor initiation assays, we show that CD117+ cells represent a CSC population. Combined, these data indicate that CD117 expression potentially promotes tumor initiation and metastasis. Further, in cell lines, CD117 activation by SCF promotes faster proliferation and invasiveness, while blocking CD117 activation with tyrosine kinase inhibitors (TKIs) decreased progression in a context-dependent manner. We demonstrate that CD117 expression and activation drives prostate cancer aggressiveness through the CSC phenotype and TKI resistance.

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