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The Nuffield Department of Surgical Sciences is the academic department of surgery at the University of Oxford, and hosts a multidisciplinary team of senior clinical academic surgeons, senior scientists, junior clinicians and scientists in training.
A polymorphism in the glucokinase gene that raises plasma fasting glucose, rs1799884, is associated with diabetes mellitus and prostate cancer: findings from a population-based, case-control study (the ProtecT study).
Epidemiological studies have identified a positive association between prostate cancer and recent onset type 2 diabetes mellitus but an increasingly inverse association with greater duration of type 2 diabetes. The mecha- nisms underlying these paradoxical associations are not clear. A single nucleotide polymorphism in the glucokinase gene, rs1799884, is associated with higher circulating plasma fasting glucose and with an increased risk of type 2 diabetes. We report a case-control study nested within the population-based Prostate testing for cancer and Treatment (ProtecT) study ISRCTN20141297. Men aged 50-69 years based around 9 UK cities were invited for a prostate specific antigen (PSA) test between June 2002 and November 2006. 1,551 cases and 2,993 controls were geno-typed. We observed suggestive evidence for a positive association between the AA variant rs1799884 and PSA-detected prostate cancer (OR(AA V GG)= 1.40, 95% CI= 0.95 to 2.07). There was little evidence that this effect was greater for more advanced stage/ grade cancers (OR(AA V GG)= 1.78, 95% CI= 0.99 to 3.21) versus less advanced cancers (OR(AA V GG)= 1.23, 95% CI= 0.77 to 1.94) (p for interaction = 0.33). The rs1799884 genotype was not associated with PSA concentration, suggesting that any effect on prostate cancer risk is not attributable to PSA detection bias. Our results provide suggestive evidence for a link between a genotype associated with type 2 diabetes mellitus and PSA-detected prostate cancer. We hypothesize that hyperglycaemia may be important in mediating this relationship.
Evaluation of association of HNF1B variants with diverse cancers: collaborative analysis of data from 19 genome-wide association studies.
BACKGROUND: Genome-wide association studies have found type 2 diabetes-associated variants in the HNF1B gene to exhibit reciprocal associations with prostate cancer risk. We aimed to identify whether these variants may have an effect on cancer risk in general versus a specific effect on prostate cancer only. METHODOLOGY/PRINCIPAL FINDINGS: In a collaborative analysis, we collected data from GWAS of cancer phenotypes for the frequently reported variants of HNF1B, rs4430796 and rs7501939, which are in linkage disequilibrium (r(2) = 0.76, HapMap CEU). Overall, the analysis included 16 datasets on rs4430796 with 19,640 cancer cases and 21,929 controls; and 21 datasets on rs7501939 with 26,923 cases and 49,085 controls. Malignancies other than prostate cancer included colorectal, breast, lung and pancreatic cancers, and melanoma. Meta-analysis showed large between-dataset heterogeneity that was driven by different effects in prostate cancer and other cancers. The per-T2D-risk-allele odds ratios (95% confidence intervals) for rs4430796 were 0.79 (0.76, 0.83)] per G allele for prostate cancer (p<10(-15) for both); and 1.03 (0.99, 1.07) for all other cancers. Similarly for rs7501939 the per-T2D-risk-allele odds ratios (95% confidence intervals) were 0.80 (0.77, 0.83) per T allele for prostate cancer (p<10(-15) for both); and 1.00 (0.97, 1.04) for all other cancers. No malignancy other than prostate cancer had a nominally statistically significant association. CONCLUSIONS/SIGNIFICANCE: The examined HNF1B variants have a highly specific effect on prostate cancer risk with no apparent association with any of the other studied cancer types.
Metabolic imbalance and prostate cancer progression.
There is substantial evidence implicating environmental factors in the progression of prostate cancer. The metabolic consequences of a western lifestyle, such as obesity, insulin resistance and abnormal hormone production have been linked to prostate carcinogenesis through multiple overlapping pathways. Insulin resistance results in raised levels of the mitogens insulin and insulin-like growth factor-1, both of which may affect prostate cancer directly, or through their effect on other metabolic regulators. Obesity is associated with abnormal levels of adipocyte-derived peptides (adipokines), sex hormones and inflammatory cytokines. Adipokines have been shown to influence prostate cancer in both cell culture studies and observational, population level studies. Testosterone appears to have a complex relationship with prostate carcinogenesis, and it has been suggested that the lower levels associated with obesity may select for more aggressive androgen independent prostate cancer cells. Prostatic inflammation, caused by infection, urinary reflux or dietary toxins, frequently occurs prior to cancer development and may influence progression to advanced disease. High levels of ω-6 fatty acids in the diet may lead to the production of further inflammatory molecules that may influence prostate cancer. Increased fatty acid metabolism occurs within tumour cells, providing a potential target for prostate cancer therapies. Aberrations in amino acid metabolism have also been identified in prostate cancer tissue, particularly in metastatic cancer. This evidence indicates lifestyle interventions may be effective in reducing the incidence of clinical disease. However, much more research is needed before recommendations are made.
PTGS2-899G>C and prostate cancer risk: a population-based nested case-control study (ProtecT) and a systematic review with meta-analysis.
Prostaglandin endoperoxidase synthase 2 is a key regulator of inflammation and may play a role in prostate carcinogenesis. The polymorphism, -899G>C (rs20417), alters a transcription factor-binding site and is associated with a reduced risk of colorectal adenoma. We tested the hypothesis that rs20417 may influence prostate cancer risk, using a large case-control study (n(cases)=1608, n(controls)=3058). We found no evidence that rs20417 alters prostate cancer risk (odds ratio (OR(CC & GC v GG)=1.05, 95% confidence interval (CI)=0.91-1.20). A meta-analysis of three studies also found little evidence that rs20417 alters risk (pooled OR(CC & GC v GG)=1.04, 95% CI=0.93-1.17), making it unlikely that rs20417 contributes in any major way to prostate cancer aetiology.
Prostate cancer proteomics: The urgent need for clinically validated biomarkers.
Prostate cancer (PCa) is the most common cancer diagnosis and the second most common cause of cancer-related deaths in men. Currently, serum prostate-specific antigen (PSA) is the only biomarker widely used in the diagnosis and management of patients with PCa. However, PSA lacks diagnostic sensitivity and specificity, leading to false-negative and false-positive test results. PSA cannot distinguish indolent from aggressive disease, leading to many patients being over-treated with associated side-effects. Furthermore, PSA is unable to identify which tumors are likely to become unresponsive to treatment at an early stage. Thus, there is an urgent need for clinically validated biomarkers which will improve the diagnosis and management of PCa. Given the heterogeneity of PCa it is likely that a panel of biomarkers will be required. In the quest for PCa biomarkers, a wide range of samples including urine, serum, tissues, and cell lines have been studied using proteomic approaches such as 2-DE, SELDI-TOF, SILAC, ICAT, iTRAQ, and MALDI-IMS. The value of these technologies, and other emerging platforms such as selected reaction monitoring (SRM) and multiple reaction monitoring (MRM), are discussed in the context of biomarker discovery, validation and addressing the "bottle-necks" that exist prior to clinical translation.
Phenotypic variations of TRAIL sensitivity in cloned populations of prostate cancer cells
Factors that regulate the induction of apoptosis of tumour cells are potential candidates for therapeutic intervention for the majority of cancers. Studying modifiers of apoptotic responses, such as members of the tumour necrosis factor receptor superfamily, may give clues as to how induction of apoptosis in tumours could be maximized to enhance the benefit of treatment regimes. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anti-tumour molecule since its activity is specific for tumour cell populations. TRAIL binds to death receptors, inducing apoptosis in susceptible cells. The mechanisms which determine whether tumour cells are susceptible to TRAIL are unclear, and several mechanisms have been proposed, including expression of osteoprotegerin (OPG), decoy receptors, and factors that affect intracellular signalling of pro-apoptotic molecules, such as c-FLIP. Here we show that experiments to modulate the activity of one of these factors, OPG, by over-expression and also by stable knockdown of OPG expression, alters the TRAIL sensitivity of PC3 prostate cancer cells. However we show that some observed effects, which appear to support the hypothesis that OPG prevents TRAIL-induced apoptosis of tumour cells, may be due to variation of the TRAIL response of sub-clones of tumour cells, even within a cloned population. These results highlight potential limitations of experiments designed to test contribution of factors affecting intrinsic apoptosis susceptibility using cloned tumour cell populations. © 2008 Wiley-Liss, Inc.
The PCPT trial
The PCPT trial is the first phase III trial with the principal objective of examining the hypothesis that the use of chemoprevention could prevent the development of prostate cancer. This is a large scale randomised clinical trial comparing finasteride (5-α reductase inhibitor) to placebo. A total of 18,882 men aged 55 years old or above with unremarkable rectal examination and serum PSA below 3 ng/ml were randomised between daily treatment with 5 mg of finasteride or placebo for 7 years. The incidence of prostate cancer diagnosed by biopsy was 24.4% in the placebo group compared to 18.4% in the finasteride group. The incidence of high Gleason grade cancers (7-10) in the finasteride group (6.4%) appeared to be higher than in the placebo group (5.1%) although it was subsequently shown that these results were not significant. Sexual adverse effects were more common in the finasteride group and urinary symptoms were more common in the placebo group than in the finasteride group. The volumes of prostates treated with finasteride were reduced by 24% compared to the placebo arm. It does not therefore appear at present appropriate to give finasteride to prevent the development of prostate cancer until more detailed results are available about the nature of the cancers which may possibly have been detected or avoided. © 2008 Elsevier Masson SAS. All rights reserved.
The spectrum of prostate cancer care: From curative intent to palliation
Prostate cancer is one of the most prevalent malignancies affecting men in the developed world. A spectrum of disease states exists and management is tailored to individual patients. Increasing public awareness and prostate-specific antigen testing have led to earlier detection and the possibility of cure but have increased the risk of overtreatment of indolent disease. Advances in curative modalities have reduced side effects and offer patients a choice of treatments. Nonetheless, many need no intervention and may be safely treated with active monitoring. Choice and timing of therapy for locally advanced and recurrent disease are variable, with potential benefits of early intervention counterbalanced by side effects of treatment. Progress has been made in the management of advanced disease; skeletal-related events have been reduced and survival has been increased. This review examines the evidence and rationale behind the treatment options from curative intent to management of locally advanced disease and palliation of metastatic disease. Copyright © 2008 by Current Medicine Group LLC.
Artificial intelligence and bladder cancer arrays.
Non-muscle invasive bladder cancer is a heterogenous disease whose management is dependent upon the risk of progression to muscle invasion. Although the recurrence rate is high, the majority of tumors are indolent and can be managed by endoscopic means alone. The prognosis of muscle invasion is poor and radical treatment is required if cure is to be obtained. Progression risk in non-invasive tumors is hard to determine at tumor diagnosis using current clinicopathological means. To improve the accuracy of progression prediction various biomarkers have been evaluated. To discover novel biomarkers several authors have used gene expression microarrays. Various statistical methods have been described to interpret array data, but to date no biomarkers have entered clinical practice. Here, we describe a new method of microarray analysis using neurofuzzy modeling (NFM), a form of artificial intelligence, and integrate it with artificial neural networks (ANN) to investigate non-muscle invasive bladder cancer array data (n=66 tumors). We develop a predictive panel of 11 genes, from 2800 expressed genes, that can significantly identify tumor progression (average Logrank p = 0.0288) in the analyzed cancers. In comparison, this panel appears superior to those genes chosen using traditional analyses (average Logrank p = 0.3455) and tumor grade (Logrank, p = 0.2475) in this non-muscle invasive cohort. We then analyze panel members in a new non-muscle invasive bladder cancer cohort (n=199) using immunohistochemistry with six commercially available antibodies. The combination of 6 genes (LIG3, TNFRSF6, KRT18, ICAM1, DSG2 and BRCA2) significantly stratifies tumor progression (Logrank p = 0.0096) in the new cohort. We discuss the benefits of the transparent NFM approach with respect to other reported methods.
Gene expression assays.
The study of the profile of gene expression in a cell or tissue at a particular moment gives an insight into the plans of the cell for protein synthesis. Recent technological advances make it possible to analyze the expression of the entire genome in a single experiment. These "gene expression assays" complement or replace previous assays which measured the gene expression of only one gene, or a select group of genes. Within this chapter we outline the development of the gene expression assay and provide examples of the wide range of disciplines in which it is used. An overview of the current technologies is given, and includes an introduction to laser capture microdissection and linear amplification of RNA, both of which have extended the application of gene expression assays. Illustrative examples in the field of cancer and neuroscience highlight the scientific achievements. This technology has made in understanding the pathogenesis of diseases, including breast cancer, Huntington's disease, and schizophrenia. With recent advances including exon arrays to investigate alternative splicing, tiling arrays to investigate novel transcription start sites, and on-chip chromatin immunoprecipitation to investigate DNA-protein interactions, the future of gene expression assays is set to further our understanding of the complexities of gene expression.
[Mutation of the FGFR3 oncogene is an independent and favorable prognostic factor for tumor-specific survival in patients with urothelial carcinoma of the upper urinary tract].
AIMS: Urothelial tumors of the upper urinary tract (UUTT) frequently display microsatellite Instability (MSI) and a distinct pathway of tumorigenesis resembling MMR-deficient colorectal cancers has been recognized for MSI-UUTT. For MSS-UUTT however oncogenic mechanisms as in bladder cancer (BC) are debated. Mutation of the oncogene FGFR3 has been linked to lower stage, lower grade and favourable clinical outcome in BC. The aim of this study was to evaluate FGFR3 mutation in MSI and MSS-UUTT. METHODS: 172 unselected UUTT were screened for MSI using the National Cancer Institute Consensus Panel and additional markers; FGFR3 status was studied using mutation analysis. Histopathological and clinical data were reviewed. RESULTS: Microsatellite status had no impact on histopathological or clinical outcome. 52/99 MSS, 10/22 MSI-low and 25/51 MSI-high UUTT displayed mut. FGFR3 respectively. Overall FGFR3 mutation was associated with favourable stage and grade (p <0.0001 and p <0.002), as 62.1% of mut. vs. 23.5 % of wt. FGFR3 UUTT were stage Ta and T1 and graded G3 in 25.3 % vs. 47.1% respectively. That effect depended on MS-status however, as FGFR3 mutation was related to lower stage (pTa and pT1) in MSS/MSI-L (mut 62.9 % vs. wt 18.7%; p <0.01) only as opposed to MSI-H (mut 60% vs. wt. 50%; p = 0,1) UUTTs and as FGFR3 mut UUTTs tended to display lower grade (G1 and G2) provided stable (mut 74,2 % vs. wt. 44.1%; p <0,01) as opposed to instable microsatellite status (mut 76 % vs. wt. 73 %; p = 0.7). There was no marked relation of MS-status or FGFR3 mutation to sex, age or tobacco-exposure; localization in the renal pelvis (p < 0.01) however was more prevalent in the FGFR3 mut group. As opposed to MSI-status FGFR3 mutation had a favourable impact on survival, as 24.1% vs. 54.2 % cancer related deaths occured in the mutated group (p <0.001); this effect was indendent on stage or MSI-status. Neither MSI- nor FGFR3-status had any influence on subsequent bladder tumors. CONCLUSIONS: FGFR3 mutation is frequent in UUTT and appears to be independent of MS-status; however it is related to significantly favourable histopathological parameters and clinical outcome in MSS cases. Thus our findings might back the notion, that MSS and MSI-UUTTs stem from different oncogenic pathways and that their differing molecular character might have some relevance. Further research is warranted to study the clinical behavior of these tumors and to evaluate a potential role for MS-status and FGFR3 as prognostic tools.