Association between air cadmium exposure and prostate cancer aggressiveness at diagnosis

2020 ◽  
Author(s):  
Vishwaarth Vijayakumar ◽  
Michael R. Abern ◽  
Jyotsna S. Jagai ◽  
André Kajdacsy-Balla
Keyword(s):  
Prostate Cancer ◽  
General Population ◽  
Cancer Progression ◽  
Cadmium Exposure ◽  
Study Cohort ◽  
Low Grade ◽  
Gleason Grade ◽  
County Level ◽  
Ambient Exposure ◽  
Cancer Aggressiveness

Abstract Background There is conflicting evidence of a relationship between cadmium exposure and prostate cancer (PC) mortality in the general population. Since most PCs are indolent and clinically inconsequential, low grade and low stage tumors may mask an association between cadmium exposure and PC mortality. Methods We collected patient data from the 2010 – 2014 Surveillance, Epidemiology, and End Results (SEER). Aggressiveness at diagnosis was defined as stage categorized as either metastatic or localized and Gleason grade as high or low. The 2011 National Air Toxics Assessment database provided county-level air cadmium concentrations. We assessed the association between ambient exposure to air cadmium and PC aggressiveness at diagnosis in the US. Odds Ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression comparing the 80 th to 20 th percentile of cadmium exposure and adjusted for age at diagnosis, sociodemographic status, smoking prevalence and overall air quality at the county-level and were stratified by race and degree of urbanization by Rural-Urban Continuum Codes (RUCC). Similar OR and CI were calculated for arsenic and lead since exposure to these metals sometimes coincide with cadmium exposure as well. Results The study cohort consisted of 230,540 cases from 493 counties. Higher air cadmium exposure was associated with an increased likelihood of metastatic PC compared to localized PC (OR 1.02, CI 1.01 – 1.03) and higher Gleason grade at diagnosis (OR 1.01, CI 1.00 – 1.02). The strongest associations were observed in nonmetropolitan areas with urban populations of 20,000 to 250,000 (RUCC2 counties): (OR 1.26, CI 1.14 – 1.39) for metastatic vs. localized PC, and (OR 1.36, CI 1.25 – 1.49) for high vs . low grade cases although these results differed somewhat by race. Compared to arsenic and lead, cadmium tended to show stronger associations with PC aggressiveness. Conclusion The strongest associations between air cadmium exposure and tumor aggressiveness were found among RUCC 2 counties, areas where 40 million Americans reside. Further studies are necessary to identify air cadmium pollution sources in these communities and to rule out additional confounding factors. Air cadmium exposure in the general population may be a more important factor than previously recognized in prostate cancer progression.

scholarly journals Observational Study of the Association between Air Cadmium Exposure and Prostate Cancer Aggressiveness at Diagnosis among a Nationwide Retrospective Cohort of 230,540 Patients in the United States

2021 ◽  
Vol 18 (16) ◽  
pp. 8333
Author(s):  
Vishwaarth Vijayakumar ◽  
Michael R. Abern ◽  
Jyotsna S. Jagai ◽  
André Kajdacsy-Balla
Keyword(s):  
Prostate Cancer ◽  
Observational Study ◽  
Gleason Score ◽  
The United States ◽  
Cadmium Exposure ◽  
Low Grade ◽  
Gleason Grade ◽  
County Level ◽  
Cancer Aggressiveness ◽  
Incidence And Mortality

Although studies have investigated cadmium and prostate cancer (PC) incidence and mortality, the role of cadmium in PC progression might be more clinically relevant. In this observational study, we assessed the association between air cadmium exposure and PC aggressiveness, with PC stage defined as metastatic or localized and Gleason grade defined as high (Gleason score ≥8) or low (Gleason score ≤6) among PC patients from the 2010–2014 US Surveillance, Epidemiology, and End Results database. The 2005 and 2011 National Air Toxics Assessment provided county-level air cadmium concentrations. Results were presented as odds ratios (OR) with 95% confidence intervals (CI) and were calculated using random intercept mixed effects logistic regression, comparing the 80th to 20th percentile of exposure. We adjusted for age, sociodemographic status, smoking prevalence, and overall air quality at the county level, and stratified by race, age, and degree of urbanization. The cohort consisted of 230,540 cases from 493 counties. Strong associations were observed in nonmetropolitan, urban areas: (OR 1.26, CI 1.14–1.39) for metastatic vs. localized and (OR 1.41, CI 1.27–1.57) for high- vs. low-grade PC where 40 million Americans reside. This study may be hypothesis-generating to inform future studies and public health measures.

scholarly journals Linking obesogenic dysregulation to prostate cancer progression

2015 ◽  
Vol 4 (4) ◽  
pp. R68-R80 ◽  
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.

scholarly journals The expression of YAP1 is increased in high-grade prostatic adenocarcinoma but is reduced in neuroendocrine prostate cancer

2019 ◽  
Author(s):  
Siyuan Cheng ◽  
Nestor Prieto-Dominguez ◽  
Shu Yang ◽  
Zachary M. Connelly ◽  
Samantha StPierre ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Hippo Pathway ◽  
Luciferase Reporter ◽  
Low Grade ◽  
Beta Catenin ◽  
High Grade ◽  
Protein Levels ◽  
Neuroendocrine Prostate Cancer ◽  
Functional Involvement

ABSTRACTBACKGROUNDAfter long-term androgen deprivation therapy, 25-30% prostate cancer (PCa) acquires an aggressive neuroendocrine (NE) phenotype. Dysregulation of YAP1, a key transcription coactivator of the Hippo pathway, has been related to cancer progression. However, its role in neuroendocrine prostate cancer (NEPC) has not been assessed.METHODSImmunohistochemistry was used to evaluate YAP1 protein levels during PCa initiation and progression. YAP1 knockdown and luciferase reporter assays were used to evaluate the ability of YAP1 to modulate Wnt/beta-Catenin signaling.RESULTSYAP1 expression was present in the basal epithelial cells in benign prostatic tissues, lost in low grade PCa, but elevated in high grade prostate adenocarcinomas. Interestingly, the expression of YAP1 was reduced/lost in both human and mouse NEPC. Finally, YAP1 knockdown in PCa cells activates Wnt/beta-Catenin signaling, which has been implicated in NE differentiation of PCa, supporting a functional involvement of the loss of YAP1 expression in NEPC development.CONCLUSIONSThe expression of YAP1 is elevated in high grade prostate adenocarcinomas while lost in NEPC. Reduced YAP1 activates Wnt/beta-Catenin signaling in PCa cells. These results suggest that when applied to PCa patients, YAP1 inhibitors shall be used with caution.

A gene expression signature to predict high-grade prostate cancer response to oxaliplatin.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 150-150
Author(s):  
Philippe Pourquier ◽  
Stephane Puyo ◽  
Pierre Richaud ◽  
Jacques Robert ◽  
Nadine Houede
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Clinical Trials ◽  
Cell Lines ◽  
Gene Expression Signature ◽  
Chemotherapeutic Agents ◽  
Low Grade ◽  
Gleason Grade ◽  
High Grade ◽  
Expression Signature

150 Background: Prostate cancer (PCa) is one of the leading causes of death from cancer in men. High Gleason grade prostate cancers are characterized by aggressive tumors with poorly differentiated cells and a high metastatic potential. They are often refractory to chemical castration but still treated with hormone therapy to which docetaxel or cabazitaxel are added when they become resistant to the anti-androgen. Despite many clinical trials with other chemotherapeutic agents, response rates remain low. Moreover, none of these trials took into account the tumor grade. Methods: We used an in silico approach to screen for drug candidates that could be used as an alternative to taxanes, based on a 86 genes signature which could distinguish between low-grade and high-grade tumors. We extracted from the NCI60 panel databases the expression profiles of the 86 genes across 60 human tumor cell lines and the corresponding in vitro cytotoxicity data of 152 drugs and looked for correlation between their expression level and cell sensitivity to each of these drugs. Results: Among the 86 genes, we identified 9 genes (PCCB, SHMT2, DPM1, RHOT2, RPL13, CD59, EIF4AI, CDKN2C, JUN) for which expression levels across the 60 cell lines was significantly correlated (p< 0.05) to oxaliplatin but not to cisplatin sensitivity. This signature was validated at the functional level since repression of each of these genes conferred a significant change in the sensitivity of PCa cell lines to oxaliplatin but not cisplatin. Conclusions: Our results provide a proof of concept that gene expression signature specific from high grade PCa could be used for the identification of alternative therapies to taxanes. They could also be used to select patients for further clinical trials and as predictive markers of response to these drugs, which represents a further step forward towards personalized therapy of PCa.

Among men with low-grade prostate cancer on prostate biopsy, the 4Kscore to predict prostate cancer aggressiveness at prostatectomy.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 65-65
Author(s):  
Bruno Nahar ◽  
Sanoj Punnen ◽  
Stephen M Zappala ◽  
Daniel Sjoberg ◽  
Dipen Parekh
Keyword(s):  
Prostate Cancer ◽  
United States ◽  
Radical Prostatectomy ◽  
Prostate Biopsy ◽  
The United States ◽  
Low Grade ◽  
Surgical Specimen ◽  
Aggressive Prostate Cancer ◽  
Free Psa ◽  
Cancer Aggressiveness

65 Background: Most men diagnosed with prostate cancer in the United States have low-grade tumors. While many of these men are good candidates for active surveillance, a proportion will have a bad outcome due to the presence of a more aggressive prostate cancer that was missed on initial biopsy. A recent study confirmed the 4Kscore accurately predicts the likelihood of aggressive cancer on prostate biopsy. We analyzed if the 4Kscore could predict the presence of more significant cancer in men with low-grade tumors on the diagnostic biopsy. Methods: A recent prospective validation of the 4Kscore was conducted at 26 sites throughout the United States. We selected men who were found to have low-grade (Gleason 6) cancer on biopsy for this analysis. The 4Kscore calculates the risk of aggressive prostate cancer on prostate biopsy by a blood test that measures levels of four kallikrein biomarkers (total PSA, free PSA, intact PSA, and human kallikrein-2) plus age, DRE findings, and prior biopsy status. We investigated whether the 4Kscore was associated with more significant cancer among men found to have Gleason 6 cancer on prostate biopsy. We also looked at a subset of these men who underwent radical prostatectomy to see if the 4Kscore was associated with prostate cancer being upgraded in the surgical specimen. Results: Among the 1,312 men enrolled in this trial, 306 men were found to have Gleason 6 cancer on prostate biopsy. The 4Kscore was significantly associated with the number of positive cores (p=0.001) and the millimeters of cancer seen (p=0.0002), with higher 4Kscores relating to more extensive cancer present on biopsy. In the subpopulation of 51 men who underwent radical prostatectomy, the median 4Kscore was significantly higher among men who had an upgrade to Gleason 7 or higher [15% (8,25)] compared to men who did not experience an upgrade [7% (4,14)] (p=0.032) in their final pathology. Conclusions: Among men with Gleason 6 prostate cancer on biopsy, the 4Kscore was associated with the prostate cancer being upgraded in the surgical specimen at radical prostatectomy. The 4Kscore test may facilitate the selection of men who can be observed versus those who should undergo immediate treatment.

scholarly journals Comparison of Gleason upgrading rates in transrectal ultrasound systematic random biopsies versus US-MRI fusion biopsies for prostate cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 57-57
Author(s):  
Arie Carneiro ◽  
Paulo Priante Kayano ◽  
Tiago Mendonça Lopez Castilho ◽  
Arjun Sivaraman ◽  
Oliver Rojas Claros ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transrectal Ultrasound ◽  
Treatment Decision ◽  
Focal Lesion ◽  
Study Cohort ◽  
Gleason Grade ◽  
Final Pathology ◽  
Random Biopsy ◽  
Group A ◽  
Group B

57 Background: US-MRI fusion biopsy (FB) showed that it improves the detection of clinically significant prostate cancer (PCa). A more accurate diagnostic method is desirable to avoid misclassification, which in turn is particularly important in appropriate decision making on treatment for PCa (active surveillance or focal therapy or radical treatment). We aimed to compare the Gleason upgrading (GU) rates and the concordance of the Gleason scores in the biopsy versus final pathology after the surgery in patients who underwent only TRUS systematic random biopsies versus US-MRI FB for PCa. Methods: A retrospective analysis of patients’ prospective collected data that underwent prostate biopsy and subsequent radical prostatectomy were included from January 2011 to June 2016 at our institution. The study cohort was divided into: US-MRI FB (Group A) and only TRUS systematic random biopsy (Group B). US-MRI FB was performed in patients who had a previous MRI with a focal lesion classified by Likert score ≥ 3, otherwise a TRUS systematic random biopsy was performed. All biopsies and surgical specimens were analyzed by the same uropathologist and MRIs were analyzed by two expert urological radiologists. Results: 73 men underwent US-MRI FB and 89 TRUS systematic random biopsy. The GU rate was higher in group B (31.5% vs 16.4%; p = 0.027). GU according to Gleason grade pattern was higher in Group B against Group A (40.4% vs 23.3%; p = 0.02). Analyses from separate Gleason grade pattern showed that Gleason score 3+4 presented less GU in group A (24.1% vs 52.6%; p = 0.043). The Bland-Altman plot analysis showed a higher bias in Group B compared to group A (-0.27 [-1.40 to 0.86] vs -0.01 [-1.42 to 1.39]). In the multivariable logistic regression the only independent predictor of GU was the use of TRUS systematic random biopsy (2.64 [1.11 – 6.28]; p = 0.024). Conclusions: The US-MRI FB appears to be related to a decrease in GU rate and an increase in the concordance between biopsy and final pathology in comparison to TRUS random biopsy, that leads to greater accuracy on diagnosis and better treatment decision.

scholarly journals Alterations in chromosome spatial compartmentalization classify prostate cancer progression

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. 

scholarly journals Random forest-based modelling to detect biomarkers for prostate cancer progression

2019 ◽  
Author(s):  
Reka Toth ◽  
Heiko Schiffmann ◽  
Claudia Hube-Magg ◽  
Franziska Büscheck ◽  
Doris Höflmayer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Methylation ◽  
Random Forest ◽  
Candidate Genes ◽  
Cancer Progression ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Classification Model ◽  
Gleason Grade ◽  
Tissue Micro Array

AbstractThe clinical course of prostate cancer (PCa) is highly variable, demanding an individualized approach to therapy and robust prognostic markers for treatment decisions. We present a random forest-based classification model to predict aggressive behaviour of PCa. DNA methylation changes between PCa cases with good or poor prognosis (discovery cohort with n=70) were used as input. The model was validated with data from two large independent PCa cohorts from the “International Cancer Genome Consortium” (ICGC) and “The Cancer Genome Atlas” (TCGA). Ranking of cancer progression-related DNA methylation changes allowed selection of candidate genes for additional validation by immunohistochemistry. We identified loss of ZIC2 protein expression, mediated by alterations in DNA methylation, as a promising novel prognostic biomarker for PCa in >12,000 tissue micro-array tumors. The prognostic value of ZIC2 proved to be independent from established clinico-pathological variables including Gleason grade, tumor stage, nodal stage and PSA. In summary, we have developed a PCa classification model, which either directly orviaexpression analyses of the identified top ranked candidate genes might help in decision making related to the treatment of prostate cancer patients.

scholarly journals Association between air cadmium exposure and prostate cancer aggressiveness at diagnosis

2020 ◽  
Vol 2020 (1) ◽  
Author(s):  
V. Vijayakumar ◽  
M.R. Abern ◽  
A. Kajdacsy-Balla ◽  
J. Jagai
Keyword(s):  
Prostate Cancer ◽  
Cadmium Exposure ◽  
Cancer Aggressiveness

scholarly journals The independent prognostic impact of the GATA2 pioneering factor is restricted to ERG-negative prostate cancer

Tumor Biology ◽  
2019 ◽  
Vol 41 (7) ◽  
pp. 101042831882481 ◽  
Author(s):  
Franziska Büscheck ◽  
Maciej Zub ◽  
Asmus Heumann ◽  
Claudia Hube-Magg ◽  
Ronald Simon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Progression ◽  
Receptor Expression ◽  
Androgen Receptor Expression ◽  
Prognostic Impact ◽  
Gleason Grade ◽  
Advanced Tumor Stage ◽  
Normal Prostate ◽  
Advanced Tumor

GATA2 is a pioneering transcription factor governing androgen receptor expression and signaling in prostate cells. To understand the prognostic potential of GATA2 assessment in prostate cancer, we analyzed nuclear GATA2 expression on an annotated tissue microarray with 12,427 prostate cancer samples. Normal prostate glands were negative to weakly positive. GATA2 staining was found in almost all prostate cancers (95%). Strong GATA2 staining was linked to advanced tumor stage, high classical and quantitative Gleason grade (p < 0.0001 each), positive nodal stage (p = 0.0116), and early biochemical recurrence (p < 0.0001). GATA2 was linked to ERG-fusion-type cancers, with strong GATA2 staining in 29% of ERG-negative and 53% of ERG-positive cancers (p < 0.0001). Separate calculations in 3854 cancers with and 4768 cancers without TMPRSS2:ERG fusion revealed that these associations with tumor phenotype and patient outcome were largely driven by the subset of ERG-negative tumors. GATA2 expression was further linked to androgen receptor expression: Only 8% of androgen receptor-negative, but 56% of strongly androgen receptor expressing cancers had strong GATA2 expression (p < 0.0001). In conclusion, the results of our study demonstrate that increasing GATA2 levels are linked to prostate cancer progression and aggressiveness. The prognostic value of GATA2 is remarkable in ERG-negative cancers. However, the upregulation of GATA2 in ERG-positive cancers makes it unsuitable as a prognostic marker in this patient subset.

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