Ecological and epidemiological studies have identified an inverse association of intensity and duration of sunlight exposure with prostate cancer, which may be explained by a reduction in vitamin D synthesis. Pigmentation traits influence sun exposure and therefore may affect prostate cancer risk. Because observational studies are vulnerable to confounding and measurement error, we used Mendelian randomization to examine the relationship of sun exposure with both prostate cancer risk and the intermediate phenotype, plasma levels of vitamin D.
We created a tanning, a skin color and a freckling score as combinations of SNPs that have been previously associated with these phenotypes. A higher score indicates propensity to burn, have a lighter skin color and freckles. The scores were tested for association with vitamin D levels (25-hydroxyvitamin-D and 1,25-dihydroxyvitamin-D) and PSA-detected prostate cancer in 3123 white British individuals enrolled in the Prostate Testing for cancer and Treatment (ProtecT) study.
The freckling score was inversely associated with 25(OH)D levels (change in 25(OH)D per score unit −0.27; 95%CI: −0.52, −0.01), and the tanning score was positively associated with prostate cancer risk (OR 1.05; 95%CI: 1.02,1.09), after adjustment for population stratification and potential confounders.
Individuals who tend to burn are more likely to spend less time in the sun and consequently have lower plasma vitamin D levels and higher susceptibility to prostate cancer.
The use of pigmentation related genetic scores is valuable for the assessment of the potential benefits of sun exposure with respect to prostate cancer risk.
pigmentation; tanning; sun exposure; vitamin D; prostate cancer
Alcohol is an established carcinogen but not an established risk factor for prostate cancer, despite some recent prospective studies suggesting increased risk among heavy drinkers. The aim of this study was to investigate the role of alcohol on prostate-specific antigen (PSA) levels and prostate cancer risk. Two thousand four hundred PSA detected prostate cancer cases and 12,700 controls matched on age and general practice were identified through a case-control study nested in the PSA-testing phase of a large UK-based randomized controlled trial for prostate cancer treatment (ProtecT). Linear and multinomial logistic regression models were used to estimate ratios of geometric means (RGMs) of PSA and relative risk ratios (RRRs) of prostate cancer by stage and grade, with 95% confidence intervals (CIs), associated with weekly alcohol intake and drinking patterns. We found evidence of lower PSA (RGM 0.98, 95% CI: 0.98–0.99) and decreased risk of low Gleason-grade (RRR 0.96; 95%CI 0.93–0.99) but increased risk of high-grade prostate cancer (RRR 1.04; 95%CI 0.99–1.08; pdifference=0.004) per 10 units/week increase in alcohol consumption, not explained by current BMI, blood pressure, comorbidities, or reverse causation. This is the first large population-based study to find evidence of lower PSA levels for increasing alcohol consumption, with potential public health implications for the detection of prostate cancer. Our results also support a modestly higher risk of high-grade disease for heavy drinkers, but require independent replication to establish the nature of the association of alcohol with low-grade disease, preferably in cohorts with a heterogeneous case-mix.
Alcohol is not an established risk factor for prostate cancer; however, the current work suggests that heavy drinking could cause a small increase in risk of the more aggressive forms. If the results are confirmed to be causal, prostate cancer risk will be added to the many long-term health risks of heavy drinking, and public health strategies will then also reduce high-risk, poorer prognosis prostate cancer. The authors also found that heavy drinkers have lower PSA levels, suggesting that heavy alcohol consumption could be used as a marker to identify men in whom some cancers might be missed.
alcohol; prostate cancer; prostate specific antigen; ProtecT, nested case–control
Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.
Epidemiological studies suggest that vitamin D protects against prostate cancer, although evidence is limited and inconsistent. We investigated associations of circulating total 25-hydroxyvitamin D (25(OH)D) with PSA-detected prostate cancer in a case-control study nested within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) quantifying the association between circulating total 25(OH)D and prostate cancer. In case-only analyses, we used unconditional logistic regression to quantify associations of total 25(OH)D with stage (advanced vs localized) and Gleason grade (high-grade (≥7) vs low-grade (<7)). Pre-determined categories of total 25(OH)D were defined as: high: ≥30ng/mL; adequate: 20-<30ng/mL; insufficient: 12-<20ng/mL; deficient: <12ng/mL. Fractional polynomials were used to investigate the existence of any U-shaped relationship. We included 1,447 prostate cancer cases (153 advanced, 469 high-grade) and 1,449 healthy controls. There was evidence that men deficient in vitamin D had a two-fold increased risk of advanced versus localized cancer (OR for deficient vs adequate total 25(OH)D=2.33, 95% CI: 1.26,4.28) and high-grade versus low-grade cancer (OR for deficient vs adequate total 25(OH)D=1.78, 95% CI: 1.15,2.77). There was no evidence of a linear association between total 25(OH)D and prostate cancer (p=0.44) or of an increased risk of prostate cancer with high and low vitamin D levels. Our study provides evidence that lower 25(OH)D concentrations were associated with more aggressive cancers (advanced versus localized cancers and high- versus low- Gleason grade), but there was no evidence of an association with overall prostate cancer risk.
Prostate cancer; vitamin D; 25-hydroxyvitamn D
Circulating insulin-like growth factor-I (IGF-I) has been studied extensively in prostate cancer, but there is still little information about IGFs and IGF binding proteins (IGFBPs) in cancers detected by the prostate-specific antigen (PSA) test. Here we report the findings of a United Kingdom-based case-control study to investigate circulating IGFs and IGFBPs in PSA-detected prostate cancer with regard to their potential associations with different cancer stages or grades. PSA testing was offered to 110,000 men aged 50-69 years from 2002-2009. Participants with an elevated level of PSA (≥ 3.0 ng/ml) underwent prostate biopsy and measurements of blood serum IGF-I, IGF-II, IGFBP-2 and IGFBP-3 obtained at recruitment. We found that serum levels of IGF-II (OR per standard deviation increase: 1.16; 95%CI 1.08,1.24;ptrend<0.001), IGFBP-2 (1.18;1.06,1.31;ptrend<0.01) and IGFBP-3 (1.27;1.19,1.36;ptrend<0.001), but not IGF-I (0.99;0.93,1.04;ptrend=0.62), were associated with PSA-detected prostate cancer. After controlling for IGFBP-3, IGF-II was no longer associated (0.99;0.91,1.08;ptrend=0.62) and IGF-I was inversely associated (0.85;0.79,0.91;ptrend<0.001) with prostate cancer. In addition, no strong associations existed with cancer stage or grade. Overall, these findings suggest potentially important roles for circulating IGF-II, IGFBP-2 and IGFBP-3 in PSA-detected prostate cancer, in support of recent in vitro evidence. While our findings for IGF-I agree with previous results from PSA-screening trials, they contrast with positive associations in routinely-detected disease, suggesting that reducing levels of circulating IGF-I might not prevent the initiation of prostate cancer but might nonetheless prevent its progression.
case-control study; insulin-like growth factors; insulin-like growth factor binding proteins; prostate cancer
It is well known that RB functions are regulated by posttranslational modifications such as phosphorylation and acetylation, but the significance of lysine methylation on RB has not been fully elucidated. Our expression analysis of SMYD2 by quantitative real-time polymerase chain reaction showed that expression levels of SMYD2 are significantly elevated in human bladder carcinomas compared with nonneoplastic bladder tissues (P < .0001), and its expression levels in tumor tissues were much higher than those of any other normal tissues. SMYD2 knockdown resulted in the suppression of cancer cell growth, and cell cycle analysis indicated that SMYD2 might play a crucial role in the G1/S transition. According to an in vitro methyltransferase assay, we found that SMYD2 methylates RB1 protein, and liquid chromatography-tandem mass spectrometry analysis revealed lysine 810 of RB1 to be methylated by SMYD2. Importantly, this methylation enhanced Ser 807/811 phosphorylation of RB1 both in vitro and in vivo. Furthermore, we demonstrated that methylated RB1 accelerates E2F transcriptional activity and promotes cell cycle progression. SMYD2 is an important oncoprotein in various types of cancer, and SMYD2-dependent RB1 methylation at lysine 810 promotes cell cycle progression of cancer cells. Further study may explore SMYD2-dependent RB1 methylation as a potential therapeutic target in human cancer.
The prevalence of specific infections in UK prostate cancer patients was investigated. Serum from 84 patients and 62 controls was tested for neutralisation of xenotropic murine leukaemia virus-related virus (XMRV) Envelope. No reactivity was found in the patient samples. In addition, a further 100 prostate DNA samples were tested for XMRV, BK virus, Trichomonas vaginalis and human papilloma viruses by nucleic acid detection techniques. Despite demonstrating DNA integrity and assay sensitivity, we failed to detect the presence of any of these agents in DNA samples, bar one sample that was weakly positive for HPV16. Therefore we conclude that these infections are absent in this typical cohort of men with prostate cancer.
Disturbed folate metabolism is associated with an increased risk of some cancers. Our objective was to determine whether blood levels of folate, vitamin B12 and related metabolites were associated with prostate cancer risk.
Matched case-control study nested within the UK population-based ProtecT study of PSA-detected prostate cancer in men aged 50–69 years. Plasma concentrations of folate, B12 (cobalamin), holo-haptocorrin, holo- and total-transcobalamin, and total homocysteine (tHcy) were measured in 1,461 cases and 1,507 controls. ProtecT study estimates for associations of folate, B12, and tHcy with prostate cancer risk were included in a meta-analysis, based on a systematic review.
In the ProtecT study, increased B12 and holo-haptocorrin concentrations showed positive associations with prostate cancer risk (highest vs lowest quartile of B12 odds ratio (OR)=1.17 (95% CI 0.95–1.43), P-for-trend=0.06; highest vs lowest quartile of holo-haptocorrin OR=1.27 (1.04–1.56), P-for-trend=0.01); folate, holo-transcobalamin and tHcy were not associated with prostate cancer risk. In the meta-analysis, circulating B12 levels were associated with an increased prostate cancer risk (pooled OR=1.10 (1.01–1.19) per 100 pmol/L increase in B12, P=0.002); the pooled OR for the association of folate with prostate cancer was positive (OR=1.11 (0.96–1.28) per 10 nmol/L, P=0.2) and conventionally statistically significant if ProtecT (the only case-control study) was excluded (OR=1.18 (1.00–1.40) per 10 nmol/L, P=0.02).
Vitamin B12 and (in cohort studies) folate were associated with increased prostate cancer risk.
Given current controversies over mandatory fortification, further research is needed to determine whether these are causal associations.
folate; vitamin B12; cobalamin; transcobalamin; haptocorrin; homocysteine; folate-mediated one-carbon metabolism; prostate cancer
Circulating vitamin B12 (cobalamin/B12) and total transcobalamin (tTC) have been associated with increased and reduced risk, respectively, of prostate cancer. Mendelian randomization has the potential to determine whether these are causal associations. We estimated associations of single nucleotide polymorphisms in B12-related genes (MTR, MTRR, FUT2, TCN2, TCN1, CUBN, and MUT) with plasma concentrations of B12, tTC, holo-transcobalamin, holo-haptocorrin, folate, and homocysteine and with prostate cancer risk in a case-control study (913 cases, 895 controls) nested within the UK-wide population-based ProtecT study of prostate cancer in men age 45-69 years. Instrumental variable (IV) analysis was used to estimate odds ratios for effects of B12 and tTC on prostate cancer. We observed that B12 was lower in men with FUT2 204G>A (rs492602), CUBN 758C>T (rs1801222) and MUT 1595G>A (rs1141321) alleles (Ptrend<0.001); tTC was lower in men with the TCN2 776C>G (rs1801198) allele (Ptrend<0.001). FUT2 204G>A and CUBN 758C>T were selected as instruments for B12; TCN2 776C>G for tTC. Conventional and IV estimates for the association of loge(B12) with prostate cancer were: OR=1.17 (95% CI 0.90-1.51), P=0.2 and OR=0.60 (0.16-2.15), P=0.4, respectively. Conventional and IV estimates for the association of loge(tTC) with prostate cancer were: OR=0.81 (0.54-1.20), P=0.3 and OR=0.41 (0.13-1.32), P=0.1, respectively. Confidence intervals around the IV estimates in our study were too wide to allow robust inference. Sample size estimates based on our data indicated that Mendelian randomization in this context requires much larger studies or multiple genetic variants that explain all of the variance in the intermediate phenotype.
Vitamin B12/cobalamin; transcobalamin; prostate cancer; Mendelian Randomization
We modelled the efficiency of a personalised approach to screening for prostate and breast cancer based on age and polygenic risk-profile compared to the standard approach based on age alone.
We compared the number of cases potentially detectable by screening in a population undergoing personalised screening with a population undergoing screening based on age alone. Polygenic disease risk was assumed to have a log-normal relative risk distribution predicted for the currently known prostate or breast cancer susceptibility variants (N=31 & N=18 respectively).
Compared to screening men based on age alone (aged 55-79: 10-year absolute risk ≥2%), personalised screening of men age 45-79 at the same risk threshold would result in 16% fewer men being eligible for screening at a cost of 3% fewer screen detectable cases, but with added benefit of detecting additional cases in younger men at high risk. Similarly, compared to screening women based on age alone (aged 47-79: 10-year absolute risk ≥2.5%), personalised screening of women age 35-79 at the same risk threshold would result in 24% fewer women being eligible for screening at a cost of 14% fewer screen detectable cases.
Personalised screening approach could improve the efficiency of screening programmes. This has potential implications on informing public health policy on cancer screening.
Polygenic risk; personalised screening; breast cancer; prostate cancer
To explore how patients' treatment preferences were expressed and justified during recruitment to a randomized controlled trial (RCT) and how they influenced participation and treatment decisions.
Study Design and Setting
Qualitative analysis of audio recordings of recruitment appointments with 93 participants aged 51–70 years in a UK multicenter RCT of localized prostate cancer treatments.
Treatment preferences at recruitment were more complex and dynamic than previously assumed. Most participants expressed views about treatments early in appointments, ranging on a continuum from hesitant to well-formed opinions. As recruiters elicited men’s views and provided detailed evidence-based treatment and study information, some opted for their preference, but many became uncertain and open to RCT recruitment, often accepting a different treatment from their original “preference.” Discussion of treatment preferences did not act as the expected barrier to recruitment but actively enabled many to express their concerns and reach an informed decision that often included RCT participation.
Exploring treatment preferences and providing evidence-based information can improve levels of informed decision making and facilitate RCT participation. Treatment preferences should be reconceptualized from a barrier to recruitment to an integral part of the information exchange necessary for informed decision making about treatments and RCT participation.
Treatment preferences; Prostate cancer; ProtecT study; Qualitative research methods; Randomized controlled trial; Recruitment to RCTs
A number of histone methyltransferases have been identified and biochemically characterized, but the pathologic roles of their dysfunction in human diseases like cancer are not well understood. Here, we demonstrate that Wolf-Hirschhorn syndrome candidate 1 (WHSC1) plays important roles in human carcinogenesis. Transcriptional levels of this gene are significantly elevated in various types of cancer including bladder and lung cancers. Immunohistochemical analysis using a number of clinical tissues confirmed significant up-regulation of WHSC1 expression in bladder and lung cancer cells at the protein level. Treatment of cancer cell lines with small interfering RNA targeting WHSC1 significantly knocked down its expression and resulted in the suppression of proliferation. Cell cycle analysis by flow cytometry indicated that knockdown of WHSC1 decreased the cell population of cancer cells at the S phase while increasing that at the G2/M phase. WHSC1 interacts with some proteins related to the WNT pathway including β-catenin and transcriptionally regulates CCND1, the target gene of the β-catenin/Tcf-4 complex, through histone H3 at lysine 36 trimethylation. This is a novel mechanism for WNT pathway dysregulation in human carcinogenesis, mediated by the epigenetic regulation of histone H3. Because expression levels of WHSC1 are significantly low in most normal tissue types, it should be feasible to develop specific and selective inhibitors targeting the enzyme as antitumor agents that have a minimal risk of adverse reaction.
EHMT2 is a histone lysine methyltransferase localized in euchromatin regions and acting as a corepressor for specific transcription factors. Although the role of EHMT2 in transcriptional regulation has been well documented, the pathologic consequences of its dysfunction in human disease have not been well understood. Here, we describe important roles of EHMT2 in human carcinogenesis. Expression levels of EHMT2 are significantly elevated in human bladder carcinomas compared with nonneoplastic bladder tissues (P < .0001) in real-time polymerase chain reaction analysis. Complementary DNA microarray analysis also revealed its overexpression in various types of cancer. The reduction of EHMT2 expression by small interfering RNAs resulted in the suppression of the growth of cancer cells and possibly caused apoptotic cell death in cancer cells. Importantly, we show that EHMT2 can suppress transcription of the SIAH1 gene by binding to its promoter region (-293 to +51) and by methylating lysine 9 of histone H3. Furthermore, an EHMT2-specific inhibitor, BIX-01294, significantly suppressed the growth of cancer cells. Our results suggest that dysregulation of EHMT2 plays an important role in the growth regulation of cancer cells, and further functional studies may affirm the importance of EHMT2 as a promising therapeutic target for various types of cancer.
Genes might have different gene interactions in different cell conditions, which might be mapped into different networks. Differential analysis of gene networks allows spotting condition-specific interactions that, for instance, form disease networks if the conditions are a disease, such as cancer, and normal. This could potentially allow developing better and subtly targeted drugs to cure cancer. Differential network analysis with direct physical gene interactions needs to be explored in this endeavour.
C3NET is a recently introduced information theory based gene network inference algorithm that infers direct physical gene interactions from expression data, which was shown to give consistently higher inference performances over various networks than its competitors. In this paper, we present, DC3net, an approach to employ C3NET in inferring disease networks. We apply DC3net on a synthetic and real prostate cancer datasets, which show promising results. With loose cutoffs, we predicted 18583 interactions from tumor and normal samples in total. Although there are no reference interactions databases for the specific conditions of our samples in the literature, we found verifications for 54 of our predicted direct physical interactions from only four of the biological interaction databases. As an example, we predicted that RAD50 with TRF2 have prostate cancer specific interaction that turned out to be having validation from the literature. It is known that RAD50 complex associates with TRF2 in the S phase of cell cycle, which suggests that this predicted interaction may promote telomere maintenance in tumor cells in order to allow tumor cells to divide indefinitely. Our enrichment analysis suggests that the identified tumor specific gene interactions may be potentially important in driving the growth in prostate cancer. Additionally, we found that the highest connected subnetwork of our predicted tumor specific network is enriched for all proliferation genes, which further suggests that the genes in this network may serve in the process of oncogenesis.
Our approach reveals disease specific interactions. It may help to make experimental follow-up studies more cost and time efficient by prioritizing disease relevant parts of the global gene network.
This study aims to validate a biostatistical approach to predict the likely effectiveness of screening in reducing advanced disease in the absence of data on incident screen and interval cancers.
We derived the predicted relative reduction in advanced stage disease following screening from the expected proportion of advanced disease following screening and the observed proportion of advanced disease detected clinically among the controls. We compared the predicted estimates to those observed in a randomised trial.
Using our method, the predicted estimates of relative reduction in node positive breast cancer following screening were comparable to the observed estimates for the age groups 50-59 and 60-69 in the screening study (predicted 32% vs. observed 40% (p=0.274) and predicted 34% vs. observed 45% (p=0.068), respectively). However, for the age groups 40-49 and 70-74 the predicted values were overestimates of the likely effectiveness of screening compared to the observed values (predicted 38% vs. observed 16% (p=0.014) and predicted 34% vs. observed 0% (p=0.001), respectively).
When the number of cancer cases is more than hundred, the method of prediction using only prevalence screen data may be accurate. Where cancers are less common, for example in small populations or young age groups, further data from interval cancers or incidence screens may be necessary.
Screening; prevalence screen; incident cancer; relative reduction; advanced cancer; overdiagnosis; prediction
Prostate-specific antigen (PSA) measurements are increasingly used to monitor men with localised prostate cancer (PCa), but there is little consensus about the method to use.
To apply age-specific predictions of PSA level (developed in men without cancer) to one cohort of men with clinically identified PCa and one cohort of men with PSA-detected PCa. We hypothesise that among men with clinically identified cancer, the annual increase in PSA level would be steeper than in men with PSA-detected cancer.
Design, setting, and participants
The Scandinavian Prostatic Cancer Group 4 (SPCG-4) cohort consisted of 321 men assigned to the watchful waiting arm of the SPCG-4 trial. The UK cohort consisted of 320 men with PSA-detected PCa in the Prostate Testing for Cancer and Treatment (ProtecT) study in nine UK centres between 1999 and 2007 who opted for monitoring rather than treatment. Multilevel models describing changes in PSA level were fitted to the two cohorts, and average PSA level at age 50, change in PSA level with age, and predicted PSA values were derived.
Results and limitations
In the SPCG-4 cohort, mean PSA at age 50 was similar to the cancer-free cohort but with a steeper yearly increase in PSA level (16.4% vs 4.0%). In the UK cohort, mean PSA level was higher than that in the cancer-free cohort (due to a PSA biopsy threshold of 3.0 ng/ml) but with a similar yearly increase in PSA level (4.1%). Predictions were less accurate for the SPCG-4 cohort (median observed minus predicted PSA level: −2.0 ng/ml; interquartile range [IQR]: −7.6–0.7 ng/ml) than for the UK cohort (median observed minus predicted PSA level: −0.8 ng/ml; IQR: −2.1–0.1 ng/ml).
In PSA-detected men, yearly change in PSA was similar to that in cancer-free men, whereas in men with symptomatic PCa, the yearly change in PSA level was considerably higher. Our method needs further evaluation but has promise for refining active monitoring protocols.
active surveillance; localised prostate cancer; PSA doubling time; PSA velocity; reference ranges
Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we have previously conducted a genome-wide association study in which 541, 129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and 1,894 controls. We have now evaluated promising associations in a second stage, in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls, and a third stage, involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to previously identified loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 (P=1.6×10−8 to P=2.7×10−33).
There is currently no means of primary prevention for prostate cancer. Increased exposure to ultraviolet-radiation may be protective, but the literature is inconclusive. We investigated associations of life-course exposure to sunlight with prostate cancer. The study design was a UK-wide nested case-control study, based on 1,020 PSA-detected cases and 5,044 matched population controls and a systematic review with meta-analysis. Men with olive/brown skin (OR= 1.47; 95% CI: 1.00 to 2.17), men who burnt rarely/never (OR= 1.11; 0.95 to 1.29) and men with the lowest levels of intense sun exposure in the 2 years prior to diagnosis (OR = 1.24; 1.03 to 1.50) had an increased prostate cancer risk. However, amongst men with prostate cancer, spending less time outside was associated with a reduced risk of advanced cancer (OR = 0.49; 0.27 to 0.89) and high Gleason grade (OR = 0.62; 0.43 to 0.91), and men who burnt rarely/never had a reduced risk of advanced cancer (OR = 0.71; 0.47 to 1.08). The meta-analysis provided weak evidence that men with the lowest (versus highest) sunlight exposure had an increased prostate cancer risk (4 studies, random-effects pooled relative risk = 1.13; 0.98 to 1.29) and higher advanced or fatal prostate cancer risk (6 studies, random-effects pooled relative risk = 1.14; 0.98 to 1.33). Our data and meta-analyses provide limited support for the hypothesis that increased exposure to sunlight may reduce prostate cancer risk. The findings warrant further investigation because of their implications for vitamin D chemoprevention trials.
Prostate cancer; sun exposure; pigmentation
Objective To examine variation in the management of prostate cancer in patients with different socioeconomic status.
Design Survey using UK regional cancer registry data.
Setting Regional population based cancer registry.
Participants 35 171 patients aged ≥51 with a diagnosis of prostate cancer, 1995-2006.
Main outcome measures Use of radiotherapy and radical surgery. Socioeconomic status according to fifths of small area deprivation index.
Results Over the nine years of the study, information on stage at diagnosis was available for 15 916 of 27 970 patients (57%). During the study period, the proportion of patients treated with radiotherapy remained at about 25%, while use of radical surgery increased significantly (from 2.9% (212/7201) during 1995-7 to 8.4% (854/10 211) during 2004-6, P<0.001). Both treatments were more commonly used in least deprived compared with most deprived patients (28.5% v 21.0% for radiotherapy and 8.4% v 4.0% for surgery). In multivariable analysis, increasing deprivation remained strongly associated with lower odds of radiotherapy or surgery (odds ratio 0.92 (95% confidence interval 0.90 to 0.94), P<0.001, and 0.91 (0.87 to 0.94), P<0.001, respectively, per incremental deprivation group). There were consistently concordant findings with multilevel models for clustering of observations by hospital of diagnosis, with restriction of the analysis to patients with information on stage, and with sequential restriction of the analysis to different age, stage, diagnosis period, and morphology groups.
Conclusions After a diagnosis of prostate cancer, men from lower socioeconomic groups were substantially less likely to be treated with radical surgery or radiotherapy. The causes and impact on survival of such differences remain uncertain.
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 (ORAA 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 (ORAA V GG= 1.78, 95% CI= 0.99 to 3.21) versus less advanced cancers (ORAA 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.
Single nucleotide polymorphisms; glucokinase; GCK; rs1799884; prostate cancer; diabetes; insulin; case-control study; prostate specific antigen
There have been few genome-wide association studies (GWAS) of prostate cancer among diverse populations. To search for novel prostate cancer risk variants, we conducted GWAS of prostate cancer in Japanese and Latinos. In addition, we tested prostate cancer risk variants and developed genetic risk models of prostate cancer for Japanese and Latinos.
Our first stage GWAS of prostate cancer included Japanese (cases/controls=1,033/1,042) and Latino (cases/controls=1,043/1,057) from the Multiethnic Cohort. Significant associations from stage 1 (P < 1.0×10−4) were examined in silico in GWAS of prostate cancer (stage 2) in Japanese (cases/controls=1,583/3,386) and Europeans (cases/controls=1,854/1,894).
No novel stage 1 SNPs outside of known risk regions reached genome-wide significance. For Japanese, in stage 1, the most notable putative novel association was seen with 10 SNPs (P<8.0. x10−6) at chromosome 2q33; however, this was not replicated in stage 2. For Latinos, the most significant association was observed with rs17023900 at the known 3p12 risk locus (stage 1: OR=1.45; P=7.01×10−5 and stage 2: OR=1.58; P =3.05×10−7). The majority of the established risk variants for prostate cancer, 79% and 88%, were positively associated with prostate cancer in Japanese and Latinos (stage I), respectively. The cumulative effects of these variants significantly influence prostate cancer risk (OR per allele=1.10; P = 2.71×10−25 and OR=1.07; P = 1.02×10−16 for Japanese and Latinos, respectively).
Conclusion and Impact
Our GWAS of prostate cancer did not identify novel genome-wide significant variants. However, our findings demonstrate that established risk variants for prostate cancer significantly contribute to risk among Japanese and Latinos.
This study aimed to assess the mean sojourn time (MST) of prostate cancer, to estimate the probability of overdiagnosis and to predict the potential reduction in advanced stage disease due to screening with PSA. The MST of prostate cancer was derived from detection rates at PSA prevalence testing in 43,842 men 50-69 years as part of the ProtecT study, from the incidence of non-screen detected cases obtained from the English population-based cancer registry database, and from PSA sensitivity obtained from the medical literature. The relative reduction in advanced stage disease was derived from the expected and observed incidence of advanced stage prostate cancer.
The age-specific MST for men aged 50-59 and 60-69 were11.3 and 12.6 years respectively. Overdiagnosis estimates increased with age; 10% to 31% of the PSA-detected cases were estimated to be overdiagnosed. An inter-screening interval of 2 years was predicted to result in 37% and 63% reduction in advanced stage disease in men 65-69 and 50-54 years respectively. If the overdiagnosed cases were excluded, the estimated reductions were 9% and 54% respectively.
Thus, the benefit of screening in reducing advanced stage disease is limited by overdiagnosis, which is greater in older men.
Prostate cancer; screening; mean sojourn time; overdiagnosis; advanced stage
This paper aims to investigate whether the stage shift (where more cancers are detected at an earlier stage) in PSA-detected cancers differs by Gleason score.
Between 2002 and 2005, 1,514 men 50-69 years were identified with prostate cancer following community-based PSA testing as part of the ProtecT study. In the same period, 2021 men 50-69 years with clinically diagnosed prostate cancer were registered at a population based cancer registry in East of England. Using logistic regression analysis and controlling for age, the odds ratio (OR) for advanced stage (TNM stage T3 and above) prostate cancer among the PSA detected group was compared to the clinically diagnosed tumours. The evidence that stage shift differs by Gleason score was assessed using the likelihood ratio test for interaction.
Advanced stage disease among the PSA detected cancers was less common than among the clinically detected cancers (OR = 0.47, 95% CI 0.39-0.56). PSA detected tumours had a substantial shift to earlier stage disease where the Gleason score was <7 (OR=0.52; 95%CI 0.36-0.77, P<0.001) but showed no such shift where the Gleason score was 7 or more (OR=0.84; 95% CI 0.66-1.07, P=0.1). There was evidence of interaction between detection mode and Gleason score (p=0.03).
The observed stage shift could be partially explained by length bias or overdiagnosis. These findings may have implications on understanding pathways of prostate cancer progression and on identifying potential targets for screening, pending further investigation of complexities of associations between PSA testing, Gleason score, and stage.
Prostate cancer; PSA testing; Stage shift; Gleason score; Effect modification
Objective To investigate the feasibility of testing for prostate cancer and the prevalence and characteristics of the disease in unselected young men.
Design Prospective cohort nested within a randomised controlled trial, with two years of follow-up.
Setting Eight general practices in a UK city.
Participants 1299 unselected men aged 45-49.
Intervention Prostate biopsies for participants with a prostate specific antigen level of 1.5 ng/ml or more and the possibility of randomisation to three treatments for those with localised prostate cancer.
Main outcome measures Uptake of testing for prostate specific antigen; positive predictive value of prostate specific antigen; and prevalence of prostate cancer, TNM disease stage, and histological grade (Gleason score).
Results 442 of 1299 men agreed to be tested for prostate specific antigen (34%) and 54 (12%) had a raised level. The positive predictive value for prostate specific antigen was 21.3%. Ten cases of prostate cancer were detected (2.3%) with eight having at least two positive results in biopsy cores and three showing perineural invasion. One tumour was of high volume (cT2c), Gleason score 7, with a positive result on digital rectal examination; nine tumours were cT1c, Gleason score 6, and eight had a negative result on digital rectal examination. Five of the nine eligible participants (55%) agreed to be randomised. No biochemical disease progression in the form of a rising prostate specific antigen level occurred in two years of follow-up.
Conclusions Men younger than 50 will accept testing for prostate cancer but at a much lower rate than older men. Using an age based threshold of 1.5 ng/ml, the prevalence of prostate cancer was similar to that in older men (3.0 ng/ml threshold) and some cancers of potential clinical significance were found.
Trial registration Current Controlled Trials ISRCTN20141297