| 1. |
- Adams, Charleen, et al.
(författare)
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Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study
- 2019
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 28:1, s. 208-216
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).MATERIALS AND METHODS: The case-control portion of the study was conducted in nine UK centres with men aged 50-69 years who underwent prostate-specific antigen (PSA) screening for prostate cancer within the Prostate testing for cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (p <0.0014, multiple-testing threshold). These fell into four classes: i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); ii) fatty acids and ratios; iii) amino acids; iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.
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| 2. |
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| 3. |
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| 4. |
- Elliott, Daisy, et al.
(författare)
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Understanding and Improving Recruitment to Randomised Controlled Trials : Qualitative Research Approaches
- 2017
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 72:5, s. 789-798
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Forskningsöversikt (refereegranskat)abstract
- Context: The importance of evidence from randomised trials is now widely recognised, although recruitment is often difficult. Qualitative research has shown promise in identifying the key barriers to recruitment, and interventions have been developed to reduce organisational difficulties and support clinicians undertaking recruitment. Objective: This article provides an introduction to qualitative research techniques and explains how this approach can be used to understand- and subsequently improve-recruitment and informed consent within a range of clinical trials. Evidence acquisition: A literature search was performed using Medline, Embase, and CINAHL. All studies with qualitative research methods that focused on the recruitment activity of clinicians were included in the review. Evidence synthesis: The majority of studies reported that organisational difficulties and lack of time for clinical staff were key barriers to recruitment. However, a synthesis of qualitative studies highlighted the intellectual and emotional challenges that arise when combining research with clinical roles, particularly in relation to equipoise and patient eligibility. To support recruiters to become more comfortable with the design and principles of randomised controlled trials, interventions have been developed, including the QuinteT Recruitment Intervention, which comprises in-depth investigation of recruitment obstacles in real time, followed by implementation of tailored strategies to address these challenges as the trial proceeds. Conclusions: Qualitative research can provide important insights into the complexities of recruitment to trials and inform the development of interventions, and provide support and training initiatives as required. Investigators should consider implementing such methods in trials expected to be challenging or recruiting below target. Patient summary: Qualitative research is a term used to describe a range of methods that can be implemented to understand participants' perspectives and behaviours. Data are gathered from interviews, focus groups, or observations. In this review, we demonstrate how this approach can be used to understand- and improve-recruitment to clinical trials. Taken together, our review suggests that healthcare professionals can find recruiting to trials challenging and require support with this process. (C) 2017 European Association of Urology. Published by Elsevier B.V.
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| 5. |
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| 6. |
- Key, Timothy J., et al.
(författare)
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Carotenoids, retinol, tocopherols, and prostate cancer risk : pooled analysis of 15 studies
- 2015
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 102:5, s. 1142-1157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Individual studies have suggested that circulating carotenoids, retinol, or tocopherols may be associated with prostate cancer risk, but the studies have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease. Objective: The objective of this study was to conduct a pooled analysis of the associations of the concentrations of 7 carotenoids, retinol, alpha-tocopherol, and gamma-tocopherol with risk of prostate cancer and to describe whether any associations differ by stage or grade of the disease or other factors. Design: Principal investigators of prospective studies provided individual participant data for prostate cancer cases and controls. Risk by study-specific fifths of each biomarker was estimated by using multivariable-adjusted conditional logistic regression in matched case-control sets. Results: Data were available for up to 11,239 cases (including 1654 advanced stage and 1741 aggressive) and 18,541 controls from 15 studies. Lycopene was not associated with overall risk of prostate cancer, but there was statistically significant heterogeneity by stage of disease, and the OR for aggressive disease for the highest compared with the lowest fifth of lycopene was 0.65 (95% CI: 0.46, 0.91; P-trend = 0.032). No other carotenoid was significantly associated with overall risk of prostate cancer or with risk of advanced-stage or aggressive disease. For retinol, the OR for the highest compared with the lowest fifth was 1.13 (95% CI: 1.04, 1.22; P-trend = 0.015). For alpha-tocopherol, the OR for the highest compared with the lowest fifth was 0.86 (95% CI: 0.78, 0.94; P-trend < 0.001), with significant heterogeneity by stage of disease; the OR for aggressive prostate cancer was 0.74 (95% CI: 0.59, 0.92; P-trend = 0.001). gamma-Tocopherol was not associated with risk. Conclusions: Overall prostate cancer risk was positively associated with retinol and inversely associated with alpha-tocopherol, and risk of aggressive prostate cancer was inversely associated with lycopene and alpha-tocopherol. Whether these associations reflect causal relations is unclear.
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| 7. |
- Law, Philip J., et al.
(författare)
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Association analyses identify 31 new risk loci for colorectal cancer susceptibility
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
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| 8. |
- Lophatananon, Artitaya, et al.
(författare)
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Height, selected genetic markers and prostate cancer risk : results from the PRACTICAL consortium.
- 2017
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 117:5, s. 734-743
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Evidence on height and prostate cancer risk is mixed, however, recent studies with large data sets support a possible role for its association with the risk of aggressive prostate cancer.METHODS: We analysed data from the PRACTICAL consortium consisting of 6207 prostate cancer cases and 6016 controls and a subset of high grade cases (2480 cases). We explored height, polymorphisms in genes related to growth processes as main effects and their possible interactions.RESULTS: The results suggest that height is associated with high-grade prostate cancer risk. Men with height >180 cm are at a 22% increased risk as compared to men with height <173 cm (OR 1.22, 95% CI 1.01-1.48). Genetic variants in the growth pathway gene showed an association with prostate cancer risk. The aggregate scores of the selected variants identified a significantly increased risk of overall prostate cancer and high-grade prostate cancer by 13% and 15%, respectively, in the highest score group as compared to lowest score group.CONCLUSIONS: There was no evidence of gene-environment interaction between height and the selected candidate SNPs.Our findings suggest a role of height in high-grade prostate cancer. The effect of genetic variants in the genes related to growth is seen in all cases and high-grade prostate cancer. There is no interaction between these two exposures.
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| 9. |
- Matejcic, Marco, et al.
(författare)
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Germline variation at 8q24 and prostate cancer risk in men of European ancestry
- 2018
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 x 10(-15)), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95% CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for similar to 25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.
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| 10. |
- Price, Alison J, et al.
(författare)
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Circulating Folate and Vitamin B12 and Risk of Prostate Cancer : A Collaborative Analysis of Individual Participant Data from Six Cohorts Including 6875 Cases and 8104 Controls.
- 2016
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 70:6, s. 941-951
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Folate and vitamin B12 are essential for maintaining DNA integrity and may influence prostate cancer (PCa) risk, but the association with clinically relevant, advanced stage, and high-grade disease is unclear.OBJECTIVE: To investigate the associations between circulating folate and vitamin B12 concentrations and risk of PCa overall and by disease stage and grade.DESIGN, SETTING, AND PARTICIPANTS: A study was performed with a nested case-control design based on individual participant data from six cohort studies including 6875 cases and 8104 controls; blood collection from 1981 to 2008, and an average follow-up of 8.9 yr (standard deviation 7.3). Odds ratios (ORs) of incident PCa by study-specific fifths of circulating folate and vitamin B12 were calculated using multivariable adjusted conditional logistic regression.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Incident PCa and subtype by stage and grade.RESULTS AND LIMITATIONS: Higher folate and vitamin B12 concentrations were associated with a small increase in risk of PCa (ORs for the top vs bottom fifths were 1.13 [95% confidence interval (CI), 1.02-1.26], ptrend=0.018, for folate and 1.12 [95% CI, 1.01-1.25], ptrend=0.017, for vitamin B12), with no evidence of heterogeneity between studies. The association with folate varied by tumour grade (pheterogeneity<0.001); higher folate concentration was associated with an elevated risk of high-grade disease (OR for the top vs bottom fifth: 2.30 [95% CI, 1.28-4.12]; ptrend=0.001), with no association for low-grade disease. There was no evidence of heterogeneity in the association of folate with risk by stage or of vitamin B12 with risk by stage or grade of disease (pheterogeneity>0.05). Use of single blood-sample measurements of folate and B12 concentrations is a limitation.CONCLUSIONS: The association between higher folate concentration and risk of high-grade disease, not evident for low-grade disease, suggests a possible role for folate in the progression of clinically relevant PCa and warrants further investigation.PATIENT SUMMARY: Folate, a vitamin obtained from foods and supplements, is important for maintaining cell health. In this study, however, men with higher blood folate levels were at greater risk of high-grade (more aggressive) prostate cancer compared with men with lower folate levels. Further research is needed to investigate the possible role of folate in the progression of this disease.
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| 11. |
- Simpkin, Andrew J, et al.
(författare)
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Development, validation and evaluation of an instrument for active monitoring of men with clinically localised prostate cancer : systematic review, cohort studies and qualitative study
- 2015
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Ingår i: Health Services and Delivery Research. - : National Institute for Health Research. - 2050-4349 .- 2050-4357. ; 3:30
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Tidskriftsartikel (refereegranskat)abstract
- Background:Active surveillance [(AS), sometimes called active monitoring (AM)],is a National Institute for Health and Care Excellence-recommended management option for men with clinically localised prostate cancer (PCa). It aims to target radical treatment only to those who would benefit most. Little consensus exists nationally or internationally about safe and effective protocols for AM/AS or triggers that indicate if or when men should move to radical treatment.Objective:The aims of this project were to review how prostate-specific antigen (PSA) has been used in AM/AS programmes; to develop and test the validity of a new model for predicting future PSA levels; to develop an instrument, based on PSA, that would be acceptable and effective for men and clinicians to use in clinical practice; and to design a robust study to evaluate the cost-effectiveness of the instrument.Methods:A systematic review was conducted to investigate how PSA is currently used to monitor men in worldwide AM/AS studies. A model for PSA change with age was developed using Prostate testing for cancer and Treatment (ProtecT) data and validated using data from two PSA-era cohorts and two pre-PSA-era cohorts. The model was used to derive 95% PSA reference ranges (PSARRs) across ages. These reference ranges were used to predict the onset of metastases or death from PCa in one of the pre-PSA-era cohorts. PSARRs were incorporated into an active monitoring system (AMS) and demonstrated to 18 clinicians and 20 men with PCa from four NHS trusts. Qualitative interviews investigated patients’ and clinicians’ views about current AM/AS protocols and the acceptability of the AMS within current practice.Results:The systematic review found that the most commonly used triggers for clinical review of PCa were PSA doubling time (PSADT) < 3 years or PSA velocity (PSAv) > 1 ng/ml/year. The model for PSA change (developed using ProtecT study data) predicted PSA values in AM/AS cohorts within 2 ng/ml of observed PSA in up to 79% of men. Comparing the three PSA markers, there was no clear optimal approach to alerting men to worsening cancer. The PSARR and PSADT markers improved the model c-statistic for predicting death from PCa by 0.11 (21%) and 0.13 (25%), respectively, compared with using diagnostic information alone [PSA, age, tumour stage (T-stage)]. Interviews revealed variation in clinical practice regarding eligibility and follow-up protocols. Patients and clinicians perceive current AM/AS practice to be framed by uncertainty, ranging from uncertainty about selection of eligible AM/AS candidates to uncertainty about optimum follow-up protocols and thresholds for clinical review/radical treatment. Patients and clinicians generally responded positively to the AMS. The impact of the AMS on clinicians’ decision-making was limited by a lack of data linking AMS values to long-term outcomes and by current clinical practice, which viewed PSA measures as one of several tools guiding clinical decisions in AM/AS. Patients reported that they would look to clinicians, rather than to a tool, to direct decision-making.Limitations:The quantitative findings were severely hampered by a lack of clinical outcomes or events (such as metastases). The qualitative findings were limited through reliance on participants’ reports of practices and recollections of events rather than observations of actual interactions.Conclusions:Patients and clinicians found that the instrument provided additional, potentially helpful, information but were uncertain about the current usefulness of the risk model we developed for routine management. Comparison of the model with other monitoring strategies will require clinical outcomes from ongoing AM/AS studies.Funding:The National Institute for Health Research Health Services and Delivery Research programme.
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| 12. |
- Simpkin, Andrew J., et al.
(författare)
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Prostate-specific antigen patterns in US and European populations : comparison of six diverse cohorts
- 2016
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Ingår i: BJU International. - : Wiley. - 1464-4096 .- 1464-410X. ; 118:6, s. 911-918
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine whether there are differences in prostate-specific antigen (PSA) levels at diagnosis or changes in PSA levels between US and European populations of men with and without prostate cancer (PCa).SUBJECTS AND METHODS: We analysed repeated measures of PSA from six clinically and geographically diverse cohorts of men: two cohorts with PSA-detected PCa, two cohorts with clinically detected PCa and two cohorts without PCa. Using multilevel models, average PSA at diagnosis and PSA change over time were compared among study populations.RESULTS: The annual percentage PSA change of 4-5% was similar between men without cancer and men with PSA-detected cancer. PSA at diagnosis was 1.7 ng/mL lower in a US cohort of men with PSA-detected PCa (95% confidence interval 1.3-2.0 ng/mL), compared with a UK cohort of men with PSA-detected PCa, but there was no evidence of a different rate of PSA change between these populations.CONCLUSION: We found that PSA changes over time are similar in UK and US men diagnosed through PSA testing and even in men without PCa. Further development of PSA models to monitor men on active surveillance should be undertaken in order to take advantage of these similarities. We found no evidence that guidelines for using PSA to monitor men cannot be passed between US and European studies.
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| 13. |
- Simpkin, Andrew J, et al.
(författare)
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Systematic Review and Meta-analysis of Factors Determining Change to Radical Treatment in Active Surveillance for Localized Prostate Cancer.
- 2015
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 67:6
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Many men with clinically localized prostate cancer are being monitored as part of active surveillance (AS) programs, but little is known about reasons for receiving radical treatment.OBJECTIVES: A systematic review of the evidence about AS was undertaken, with a meta-analysis to identify predictors of radical treatment.EVIDENCE ACQUISITION: A comprehensive search of the Embase, MEDLINE and Web of Knowledge databases to March 2014 was performed. Studies reporting on men with localized prostate cancer followed by AS or monitoring were included. AS was defined where objective eligibility criteria, management strategies, and triggers for clinical review or radical treatment were reported.EVIDENCE SYNTHESIS: The 26 AS cohorts included 7627 men, with a median follow-up of 3.5 yr (range of medians 1.5-7.5 yr). The cohorts had a wide range of inclusion criteria, monitoring protocols, and triggers for radical treatment. There were eight prostate cancer deaths and five cases of metastases in 24,981 person-years of follow-up. Each year, 8.8% of men (95% confidence interval 6.7-11.0%) received radical treatment, most commonly because of biopsy findings, prostate-specific antigen triggers, or patient choice driven by anxiety. Studies in which most men changed treatment were those including only low-risk Gleason score 6 disease and scheduled rebiopsies.CONCLUSIONS: The wide variety of AS protocols and lack of robust evidence make firm conclusions difficult. Currently, patients and clinicians have to make judgments about the balance of risks and benefits in AS protocols. The publication of robust evidence from randomized trials and longer-term follow-up of cohorts is urgently required.PATIENT SUMMARY: We reviewed 26 studies of men on active surveillance for prostate cancer. There was evidence that studies including men with the lowest risk disease and scheduled rebiopsy had higher rates of radical treatment.
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| 14. |
- Szulkin, Robert, et al.
(författare)
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Prediction of individual genetic risk to prostate cancer using a polygenic score.
- 2015
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 75:13, s. 1467-74
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction.METHODS: We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls.RESULTS: The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk.CONCLUSIONS: Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction.
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| 15. |
- Tarish, Firas L., et al.
(författare)
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Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand break repair
- 2015
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 7:312
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Tidskriftsartikel (refereegranskat)abstract
- Chemical castration improves responses to radiotherapy in prostate cancer, but the mechanism is unknown. We hypothesized that this radiosensitization is caused by castration-mediated down-regulation of non-homologous end joining (NHEJ) repair of DNA double-strand breaks (DSBs). To test this, we enrolled 48 patients with localized prostate cancer in two arms of the study: either radiotherapy first or radiotherapy after neoadjuvant castration treatment. We biopsied patients at diagnosis and before and after castration and radiotherapy treatments to monitor androgen receptor, NHEJ, and DSB repair in verified cancer tissue. We show that patients receiving neoadjuvant castration treatment before radiotherapy had reduced amounts of the NHEJ protein Ku70, impaired radiotherapy-induced NHEJ activity, and higher amounts of unrepaired DSBs, measured by gamma-H2AX foci in cancer tissues. This study demonstrates that chemical castration impairs NHEJ activity in prostate cancer tissue, explaining the improved response of patients with prostate cancer to radiotherapy after chemical castration.
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| 16. |
- Travis, Ruth C., et al.
(författare)
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A Meta-analysis of Individual Participant Data Reveals an Association between Circulating Levels of IGF-I and Prostate Cancer Risk
- 2016
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 76:8, s. 2288-2300
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Tidskriftsartikel (refereegranskat)abstract
- The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (P-trend all <= 0.005), and IGFBP-1 was inversely associated weakly with risk (P-trend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (P-heterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, P-heterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development.
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| 17. |
- Verrill, Clare, et al.
(författare)
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Altered expression of epithelial-to-mesenchymal transition proteins in extraprostatic prostate cancer.
- 2015
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553.
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Tidskriftsartikel (refereegranskat)abstract
- Epithelial to mesenchymal transition (EMT) of cancer cells involves loss of epithelial polarity and adhesiveness, and gain of invasive and migratory mesenchymal behaviours. EMT occurs in prostate cancer (PCa) but it is unknown whether this is in specific areas of primary tumours. We examined whether any of eleven EMT-related proteins have altered expression or subcellular localisation within the extraprostatic extension component of locally advanced PCa compared with other localisations, and whether similar changes may occur in in vitro organotypic PCa cell cultures and in vivo PCa models. Expression profiles of three proteins (E-cadherin, Snail, and α-smooth muscle actin) were significantly different in extraprostatic extension PCa compared with intra-prostatic tumour, and 18/27 cases had an expression change of at least one of these three proteins. Of the three significantly altered EMT proteins in pT3 samples, one showed similar significantly altered expression patterns in in vitro organotypic culture models, and two in in vivo Pten-/- model samples. These results suggest that changes in EMT protein expression can be observed in the extraprostatic extension component of locally invasive PCa. The biology of some of these changes in protein expression may be studied in certain in vitro and in vivo PCa models.
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| 18. |
- Vickers, Andrew, et al.
(författare)
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Properties of the 4-Kallikrein Panel Outside the Diagnostic Gray Zone : Meta-Analysis of Patients with Positive Digital Rectal Examination or Prostate Specific Antigen 10 ng/ml and Above
- 2017
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Ingår i: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 0022-5347 .- 1527-3792. ; 197, s. 607-613
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The 4-kallikrein panel, commercially available as the 4Kscore™, is a reflex test for prostate cancer early detection that has been extensively validated in multiple international cohorts. It has been suggested that use of such reflex tests be limited to those with prostate specific antigen less than 10 ng/ml and negative digital rectal examination. We aimed to determine the value of the panel in men outside this "diagnostic gray zone.". Materials and Methods: We performed an individual patient data meta-analysis using data from prior studies on the 4-kallikrein panel. We calculated the properties of the panel for predicting high grade (Gleason 7+) cancer in a subgroup of men with either positive digital rectal examination or prostate specific antigen 10 to 25 ng/ml. Results: A total 2,891 men from 8 cohorts were included. An important proportion of patients, including 32% in the United States validation study, had prostate specific antigen 10 to 25 ng/ml or a positive digital rectal examination. For men with prostate specific antigen 10 to 25 ng/ml the fixed-effects estimate for the discrimination of the kallikrein model was 0.84 vs 0.69 for the base model (difference 0.128, 95% CI 0.098-0.159). In the positive digital rectal examination group discrimination was 0.82 vs 0.72 (difference 0.092, 95% CI 0.069-0.115). Decision analysis showed a clinical net benefit for use of the panel in this subgroup with a reduction in biopsy rates of about 20% and only a small number of high grade cancers missed, fewer than 3% of those not biopsied. Conclusion: The use of the kallikrein panel in men with a positive digital rectal examination or prostate specific antigen 10 to 25 ng/ml is justified.
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| 19. |
- Vickers, Andrew, et al.
(författare)
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Value of Intact Prostate Specific Antigen and Human Kallikrein 2 in the 4 Kallikrein Predictive Model : An Individual Patient Data Meta-Analysis
- 2018
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Ingår i: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 0022-5347 .- 1527-3792. ; 199:6, s. 1470-1474
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The 4 kallikrein panel, commercially available as the 4Kscore®, is a statistical model that has been shown to accurately predict Gleason Grade Group 2 or greater (high grade) cancer on biopsy and the long-term risk of distant prostate cancer metastases. The panel includes 2 novel markers, namely intact prostate specific antigen and hK2. It has been questioned whether these 2 additional markers add discrimination to the clinical predictors of patient age, digital rectal examination and prior biopsy, and the established molecular markers total and free prostate specific antigen. Materials and Methods: We performed an individual patient data meta-analysis of published studies in which the 4 kallikrein panel was measured in men undergoing prostate biopsy. We assess the improvement in discrimination associated with including intact prostate specific antigen and hK2 along with total and free prostate specific antigen in the statistical model. Results: Included in analysis were 14,510 men from a total of 10 studies. The fixed effects meta-analytical estimate of the discrimination of the model without intact prostate specific antigen and hK2 was 0.742 (95% CI 0.727–0.756) compared to 0.813 (95% CI 0.801–0.825) for the full kallikrein model. The 95% CIs did not overlap and the difference in discrimination was highly statistically significant (0.069, 95% CI 0.057–0.080, p <0.0001). Intact prostate specific antigen (increase in discrimination 0.059, 95% CI 0.050–0.069) and hK2 (increase in discrimination 0.024, 95% CI 0.020–0.029, each p <0.0001) added independently to the model. Conclusions: The clinical value of the panel could not be replicated using data readily available to urologists without measuring intact prostate specific antigen and hK2.
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| 20. |
- Walsh, Eleanor I, et al.
(författare)
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Characteristics of men responding to an invitation to undergo testing for prostate cancer as part of a randomised trial.
- 2016
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Ingår i: Trials. - : Springer Science and Business Media LLC. - 1745-6215. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Sociodemographic characteristics are associated with participating in cancer screening and trials. We compared the characteristics of those responding with those not responding to a single invitation for prostate-specific antigen (PSA) testing for prostate cancer as part of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP).METHODS: Age, rurality and deprivation among 197,763 men from 271 cluster-randomised primary care centres in the UK were compared between those responding (n = 90,300) and those not responding (n = 100,953) to a prostate cancer testing invitation.RESULTS: There was little difference in age between responders and nonresponders. Responders were slightly more likely to come from urban rather than rural areas and were slightly less deprived than those who did not respond.CONCLUSION: These data indicate similarities in age and only minor differences in deprivation and urban location between responders and nonresponders. These differences were smaller, but in the same direction as those observed in other screening trials.TRIAL REGISTRATION: ISRCTN92187251 . Registered on 29 November 2004.
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| 21. |
- Watts, Eleanor L., et al.
(författare)
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The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF‐I, IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 in a pooled analysis of 16,024 men from 22 studies
- 2019
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 145:12, s. 3244-3256
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Tidskriftsartikel (refereegranskat)abstract
- Insulin‐like growth factors (IGFs) and insulin‐like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross‐sectional associations of these exposures with circulating concentrations of IGFs (IGF‐I and IGF‐II) and IGFBPs (IGFBP‐1, IGFBP‐2 and IGFBP‐3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22–89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGF‐I, IGF‐II and IGFBP‐3. Higher body mass index was associated with lower concentrations of IGFBP‐1 and IGFBP‐2. Taller height was associated with higher concentrations of IGF‐I and IGFBP‐3 and lower concentrations of IGFBP‐1. Smokers had higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGFBP‐3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF‐II and lower concentrations of IGF‐I and IGFBP‐2. African Americans had lower concentrations of IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 and Hispanics had lower IGF‐I, IGF‐II and IGFBP‐3 than non‐Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.
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| 22. |
- Wu, Lang, et al.
(författare)
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Identification of Novel Susceptibility Loci and Genes for Prostate Cancer Risk : A Transcriptome-Wide Association Study in over 140,000 European Descendants
- 2019
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 79:13, s. 3192-3204
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association study-identified prostate cancer risk variants explain only a relatively small fraction of its familial relative risk, and the genes responsible for many of these identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project, we established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets. We identified significant associations for 137 genes at P < 2.61 x 10(-6), a Bonferroni-corrected threshold, including nine genes that remained significant at P < 2.61 x 10(-6) after adjusting for all known prostate cancer risk variants in nearby regions. Of the 128 remaining associated genes, 94 have not yet been reported as potential target genes at known loci. We silenced 14 genes and many showed a consistent effect on viability and colony-forming efficiency in three cell lines. Our study provides substantial new information to advance our understanding of prostate cancer genetics and biology. Significance: This study identifies novel prostate cancer genetic loci and possible causal genes, advancing our understanding of the molecular mechanisms that drive prostate cancer.
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