Circulating 25‐hydroxyvitamin D,vitamin D‐binding protein and risk of prostate cancer

We recently reported a significant positive association between 25‐hydroxyvitamin D [25(OH)D], the accepted biomarker of vitamin D status, and prostate cancer risk. To further elucidate this association, we examined the influence of vitamin D‐binding protein (DBP), the primary transporter of vitamin D compounds in the circulation. Prediagnostic serum concentrations of DBP were assayed for 950 cases and 964 matched controls with existing 25(OH)D measurements within the Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention Study of Finnish men. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), and statistical tests were two sided. Serum DBP modified the association between serum 25(OH)D and prostate cancer, with higher risk for elevated 25(OH)D levels observed primarily among men having DBP concentrations above the median (OR = 1.81, 95% CI: 1.18–2.79 for highest vs. lowest quintile, p‐trend = 0.001) compared to those with DBP below the median (OR = 1.22, 95% CI: 0.81–1.84, p‐trend 0.97; p‐interaction = 0.04). Serum DBP was not associated with prostate cancer risk overall (OR = 0.96, 95% CI: 0.70–1.33 for highest vs. lowest quintile); however, high serum DBP was associated with significantly decreased risk of prostate cancer in men with lower (<median) 25(OH)D concentrations (OR = 0.59, 95% CI: 0.38–0.90 for highest vs. lowest quintile, p‐trend = 0.003) and increased risk in men with higher 25(OH)D concentrations (OR = 1.47, 95% CI: 0.98–2.20, p‐trend 0.10, p‐interaction = 0.02). Our data suggest that the primary vitamin D carrier protein, DBP, modulates the impact of vitamin D status on prostate cancer.     

Fatherhood status and risk of prostate cancer: Nationwide,population‐based case–control study

Previous studies have shown a decreased risk of prostate cancer for childless men; however, the cause of the association remains to be elucidated. The aim of our study was to assess the risk of prostate cancer by fatherhood status, also considering potential confounding factors. In a case–control study in Prostate Cancer data Base Sweden 2.0, a nationwide, population‐based cohort, data on number of children, marital status, education, comorbidity and tumor characteristics obtained through nationwide healthcare registers and demographic databases for 117,328 prostate cancer cases and 562,644 controls, matched on birth year and county of residence, were analyzed. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for prostate cancer overall and by risk category, adjusting for marital status and education. Childless men had a decreased risk of prostate cancer compared to fathers, OR = 0.83 (95% CI = 0.82–0.84), and risk was lower for low‐risk prostate cancer, OR = 0.74 (95% CI = 0.72–0.77), than for metastatic prostate cancer, OR = 0.93 (95% CI = 0.90–0.97). Adjustment for marital status and education attenuated the association in the low‐risk category, adjusted OR = 0.87 (95% CI = 0.84–0.91), whereas OR for metastatic cancer remained virtually unchanged, adjusted OR = 0.92 (95% CI = 0.88–0.96). Our data indicate that the association between fatherhood status and prostate cancer to a large part is due to socioeconomic factors influencing healthcare‐seeking behavior including testing of prostate‐specific antigen levels.     

Methylation in benign prostate and risk of disease progression in men subsequently diagnosed with prostate cancer

In DNA from prostate tumors, methylation patterns in gene promoter regions can be a biomarker for disease progression. It remains unclear whether methylation patterns in benign prostate tissue—prior to malignant transformation—may provide similar prognostic information. To determine whether early methylation events predict prostate cancer outcomes, we evaluated histologically benign prostate specimens from 353 men who eventually developed prostate cancer and received “definitive” treatment [radical prostatectomy (58%) or radiation therapy (42%)]. Cases were drawn from a large hospital‐based cohort of men with benign prostate biopsy specimens collected between 1990 and 2002. Risk of disease progression associated with methylation was estimated using time‐to‐event analyses. Average follow‐up was over 5 years; biochemical recurrence (BCR) occurred in 91 cases (26%). In White men, methylation of the APC gene was associated with increased risk of BCR, even after adjusting for standard clinical risk factors for prostate cancer progression (adjusted hazard ratio (aHR) = 2.26; 95%CI 1.23–4.16). APC methylation was most strongly associated with a significant increased risk of BCR in White men with low prostate specific antigen at cohort entry (HR = 3.66; 95%CI 1.51–8.85). In additional stratified analyses, we found that methylation of the RARB gene significantly increased risk of BCR in African American cases who demonstrated methylation of at least one of the other four genes under study (HR = 3.80; 95%CI 1.07–13.53). These findings may have implications in the early identification of aggressive prostate cancer as well as reducing unnecessary medical procedures and emotional distress for men who present with markers of indolent disease.     

Risk of prostate cancer among Swedish‐born and foreign‐born men in Sweden, 1961–2004

To elucidate the importance of environmental and genetic factors in prostate cancer etiology, we compared the risk of prostate cancer among foreign‐born men to that of Swedish‐born men in Sweden and to that in the country of origin. We estimated rate ratios (RRs) with 95% confidence intervals (CIs) adjusted for age, calendar period of year and education using Poisson regression in a cohort of 3.8 million men aged 45 years and older between 1961 and 2004. During the 45 years of follow‐up, 8,244 and 187,675 cases of prostate cancer occurred among foreign‐born and Swedish‐born men, respectively. Overall, foreign‐born men had a significantly 40% decreased risk of prostate cancer compared to Swedish‐born men (RR = 0.62, 95% CI = 0.61–0.63). Men born in Middle Africa and in the Caribbean had an increased risk (RR = 1.89, 95% CI = 0.95–3.78 and RR = 1.24, 95% CI = 0.71–2.19, respectively). The overall risk in both strata of duration of residence or age at immigration was lower among immigrants compared to Swedish‐born men. After additional adjustment for birthplace and age at immigration, although the risk remained lower among immigrants compared to Swedish‐born, but it was increased among immigrants who stayed 35 years and longer compared to those who stayed shorter (RR = 1.33, 95% CI = 1.21–1.46). Both environmental and genetic factors seem to be involved in the etiology of prostate cancer. Duration of residence was an important factor affecting the risk among immigrants. Studies focusing on the etiology of prostate cancer specifically in African immigrants and their descendants and increasing preventive and diagnostic activities on old immigrants are recommended. © 2008 Wiley‐Liss, Inc.     

Plasma insulin‐like growth factor 1 is positively associated with low‐grade prostate cancer in the Health Professionals Follow‐up Study 1993–2004

The insulin‐like growth factor (IGF) axis plays a role in growth and progression of prostate cancer. High circulating IGF‐1 levels have been associated with an increased risk of prostate cancer. Results for IGF binding protein 3 (IGFBP‐3) are inconclusive. Some studies have indicated that the positive association with IGF‐1 is observed only for low‐grade prostate cancer (Gleason sum < 7). We previously reported in the Health Professionals Follow‐up Study (HPFS) a direct positive association between ELISA‐measured plasma IGF‐1 and IGFBP‐3 and risk of prostate cancer (462 cases diagnosed after providing a blood specimen (between 1993 and 1995), but before February 1998). With additional follow‐up through January 31st 2004, and 1,331 case–control pairs in total, we were now able to investigate low‐grade (Gleason sum < 7, n = 635) and high‐grade (Gleason sum ≥ 7, n = 515) prostate cancer separately. Matched odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. ORs of total prostate cancer comparing top to bottom quartiles were 1.41 (95% CI 1.12–1.78, p‐trend = 0.001) for IGF‐1 and 1.58 (95% CI 1.24–2.01, p‐trend = 0.003) for IGFBP‐3. IGF‐1 was more strongly associated with low‐grade (OR = 1.61 top versus bottom quartile, 95% CI 1.16–2.25, p‐trend = 0.01), than with high‐grade (OR = 1.29, 95% CI 0.89–1.88, p‐trend = 0.12) prostate cancer (p‐heterogeneity = 0.08). We hypothesize that these findings reflect that high‐grade prostate cancers are more autonomous, and, thus, less sensitive to the action of IGF‐1 than low‐grade cancers.     

Prediagnostic plasma IGFBP‐1, IGF‐1 and risk of prostate cancer

Insulin‐like growth factor (IGF)?1 is associated with a higher risk of prostate cancer. IGF‐binding protein (IGFBP)?1, a marker for insulin activity, also binds IGF‐1 and inhibits its action. Data on IGFBP‐1 and prostate cancer risk are sparse and whether the IGF and insulin axes interact to affect prostate cancer carcinogenesis is unknown. We evaluated the independent and joint influence of prediagnostic plasma levels of IGFBP‐1 (fasting) and IGF‐1 on risk of prostate cancer among 957 cases and 1,021 controls with fasting levels of IGFBP‐1 and 1,709 cases and 1,778 controls with IGF‐1 nested within the Health Professionals Follow‐up Study. Unconditional logistic regression adjusting for matching factors was used to estimate the odds ratio (OR) and 95% confidence interval (CI). Higher prediagnostic fasting IGFBP‐1 levels were associated with lower risk of prostate cancer (highest vs. lowest quartile OR = 0.67, 95% CI 0.52–0.86, p_trend = 0.003), which remained similar after adjusting for IGF‐1. Prediagnostic IGF‐1 was associated with increased risk of prostate cancer (highest vs. lowest quartile OR = 1.28, 95% CI = 1.05–1.56, p_trend = 0.01). The associations with each marker were primarily driven by lower‐grade and non‐advanced prostate cancer. Being low in IGFBP‐1 and high in IGF‐1 did not confer appreciable additional risk (p_interaction = 0.42). In summary, prediagnostic fasting IGFBP‐1 may influence prostate cancer carcinogenesis. Being low in IGFBP‐1 or high in IGF‐1 is sufficient to elevate the risk of prostate cancer.     

Effects of α‐tocopherol and β‐carotene supplementation on cancer incidence and mortality: 18‐Year postintervention follow‐up of the Alpha‐Tocopherol,Beta‐Carotene Cancer Prevention Study

In the Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention Study among 29,133 Finnish male smokers aged 50–69 years, daily α‐tocopherol (50 mg) for a median of 6.1 years decreased the risk of prostate cancer, whereas β‐carotene (20 mg) increased risk of lung cancer and overall mortality. To determine the postintervention effects of α‐tocopherol and β‐carotene, 25,563 men were followed 18 years for cancer incidence and all causes of mortality through national registers. Neither supplement had significant effects on post‐trial cancer incidence. Relative risk (RR) for lung cancer (n = 2,881) was 1.04 (95% confidence interval [CI], 0.96–1.11) among β‐carotene recipients compared with nonrecipients. For prostate cancer (n = 2,321), RR was 0.97 (95% CI, 0.89–1.05) among α‐tocopherol recipients compared with nonrecipients with the preventive effect of α‐tocopherol continuing ～8 years postintervention. Body mass index significantly modified the effect of α‐tocopherol on prostate cancer (p for interaction = 0.01) RR 1.00 (95% CI, 0.88–1.14) in normal‐weight men, 0.87 (95% CI, 0.77–0.98) in overweight men, and 1.25 (95% CI, 1.01–1.55) in obese men. The post‐trial relative mortality (based on 16,686 deaths) was 1.02 (95% CI, 0.98–1.05) for α‐tocopherol recipients compared with nonrecipients and 1.02 (95% CI, 0.99–1.05) for β‐carotene recipients compared with nonrecipients. α‐Tocopherol decreased post‐trial prostate cancer mortality (RR, 0.84; 95% CI, 0.70–0.99), whereas β‐carotene increased it (RR, 1.20; 95% CI, 1.01–1.42). In conclusion, supplementation with α‐tocopherol and β‐carotene appeared to have no late effects on cancer incidence. The preventive effect of moderate‐dose α‐tocopherol on prostate cancer continued several years post‐trial and resulted in lower prostate cancer mortality.     

Metabolomic analysis of prostate cancer risk in a prospective cohort: The alpha‐tocopherol,beta‐carotene cancer prevention (ATBC) study

Despite decades of concerted epidemiological research, relatively little is known about the etiology of prostate cancer. As genome‐wide association studies have identified numerous genetic variants, so metabolomic profiling of blood and other tissues represents an agnostic, “broad‐spectrum” approach for examining potential metabolic biomarkers of prostate cancer risk. To this end, we conducted a prospective analysis of prostate cancer within the Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention Study cohort based on 200 cases (100 aggressive) and 200 controls (age‐ and blood collection date‐matched) with fasting serum collected up to 20 years prior to case diagnoses. Ultrahigh performance liquid chromatography/mass spectroscopy and gas chromatography/mass spectroscopy identified 626 compounds detected in >95% of the men and the odds ratio per 1‐standard deviation increase in log‐metabolite levels and risk were estimated using conditional logistic regression. We observed strong inverse associations between energy and lipid metabolites and aggressive cancer (p = 0.018 and p = 0.041, respectively, for chemical class over‐representation). Inositol‐1‐phosphate showed the strongest association (OR = 0.56, 95% CI = 0.39–0.81, p = 0.002) and glycerophospholipids and fatty acids were heavily represented; e.g., oleoyl‐linoleoyl‐glycerophosphoinositol (OR = 0.64, p = 0.004), 1‐stearoylglycerophosphoglycerol (OR=0.65, p = 0.025), stearate (OR=0.65, p = 0.010) and docosadienoate (OR = 0.66, p = 0.014). Both alpha‐ketoglutarate and citrate were associated with aggressive disease risk (OR = 0.69, 95% CI = 0.51–0.94, p = 0.02; OR = 0.69, 95% CI = 0.50–0.95, p = 0.02), as were elevated thyroxine and trimethylamine oxide (OR = 1.65, 95% CI = 1.08–2.54, p = 0.021; and OR = 1.36, 95% CI = 1.02–1.81, p = 0.039). Serum PSA adjustment did not alter the findings. Our data reveal several metabolomic leads that may have pathophysiological relevance to prostate carcinogenesis and should be examined through additional research.     

Sarcosine and other metabolites along the choline oxidation pathway in relation to prostate cancer—A large nested case–control study within the JANUS cohort in Norway

Methyl group donors and intermediates of one‐carbon metabolism affect DNA synthesis and DNA methylation, and may thereby affect prostate carcinogenesis. Choline, the precursor of betaine, and the one‐carbon metabolite sarcosine have been associated with increased prostate cancer risk. Within JANUS, a prospective cohort in Norway (n = 317,000) with baseline serum samples, we conducted a nested case–control study among 3,000 prostate cancer cases and 3,000 controls. Using conditional logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) for prostate cancer risk were estimated according to quintiles of circulating betaine, dimethylglycine (DMG), sarcosine, glycine and serine. High sarcosine and glycine concentrations were associated with reduced prostate cancer risk of borderline significance (sarcosine: highest vs. lowest quintile OR = 0.86, CI = 0.72–1.01, p_trend = 0.03; glycine: OR = 0.83, CI = 0.70–1.00, p_trend = 0.07). Serum betaine, DMG and serine were not associated with prostate cancer risk. However, individuals with a high glycine/serine ratio were at decreased prostate cancer risk (OR = 0.74, CI = 0.69–0.85, p_trend < 0.001). This population‐based study suggested that men with high serum sarcosine or glycine concentrations have modestly reduced prostate cancer risk. Ratios of metabolites reflecting one‐carbon balance may be associated with prostate cancer risk, as demonstrated for the glycine/serine ratio, and should be explored in future studies.     

A 24‐year prospective study of dietary α‐linolenic acid and lethal prostate cancer

Several meta‐analyses have attempted to determine the relationships between intake of α‐linolenic acid (ALA) and prostate cancer, but results were inconclusive. 47,885 men aged 40–75 years without prior cancer in the Health Professionals Follow‐Up Study were prospectively followed from 1986 to 2010. Intake of ALA was determined from validated food frequency questionnaires every 4 years. We used multivariate Cox proportional hazards models to estimate hazard ratios (HR) with 95% confidence intervals (CIs) for lethal prostate cancer (distant metastasis or prostate cancer death). 386 lethal prostate cancers were diagnosed in the pre‐PSA era (before February, 1994) and 403 cancers in the PSA era. Intake of ALA was associated with increased risk of lethal prostate cancer in the pre‐PSA era (comparing top to bottom quintile of intake, multivariate‐adjusted HR = 1.78; 95% CI = 1.22–2.06; p_trend = 0.003), but not in the PSA era (HR = 0.81; 95% CI = 0.56–1.17; p_trend = 0.53), and the difference in associations was statistically significant (p for interaction = 0.02). Mayonnaise, a primary food source of ALA intake in our cohort, was likewise only significantly associated with lethal prostate cancer in the pre‐PSA era. Among many other fatty acids that are correlated with ALA due to shared food sources, none was associated with lethal prostate cancer in the pre‐PSA era. In conclusion, higher intake of ALA was associated with an increased risk of lethal prostate cancer in the pre‐PSA era, but not in the PSA era. Potential reasons for the differential associations warrant further investigation.     

Life course sun exposure and risk of prostate cancer: Population‐based nested case‐control study and meta‐analysis

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 prostate specific antigen‐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. © 2009 UICC     

Associations of aspirin,nonsteroidal anti‐inflammatory drug and paracetamol use with PSA‐detected prostate cancer: Findings from a large,population‐based,case–control study (the ProtecT study)

Evidence from laboratory studies suggests that chronic inflammation plays an important role in prostate cancer aetiology. This has resulted in speculation that nonsteroidal anti‐inflammatory drugs may protect against prostate cancer development. We analysed data from a cross‐sectional case–control study (n_cases= 1,016; n_controls= 5,043), nested within a UK‐wide population‐based study that used prostate specific antigen (PSA) testing for identification of asymptomatic prostate cancers, to investigate the relationship of aspirin, nonsteroidal anti‐inflammatory drug (NSAID) and paracetamol use with prostate cancer. In conditional logistic regression models accounting for stratum matching on age (5‐year age bands) and recruitment centre, use of non‐aspirin NSAIDs [odds ratio (OR) = 1.32; 95% confidence interval (CI): 1.04–1.67] or all NSAIDs (OR = 1.25; 95% CI = 1.07–1.47) were positively associated with prostate cancer. There were weaker, not conventionally statistically significant, positive associations of aspirin (OR = 1.13; 95% CI = 0.94–1.36) and paracetamol (OR = 1.20; 95% CI = 0.90–1.60) with prostate cancer. Mutual adjustment for aspirin, non‐aspirin NSAIDs or paracetamol made little difference to these results. There was no evidence of confounding by age, family history of prostate cancer, body mass index or self‐reported diabetes. Aspirin, NSAID and paracetamol use were associated with reduced serum PSA concentrations amongst controls. Our findings do not support the hypothesis that NSAIDs reduce the risk of PSA‐detected prostate cancer. Our conclusions are unlikely to be influenced by PSA detection bias because the inverse associations of aspirin, NSAID and paracetamol use with serum PSA would have attenuated (not generated) the observed positive associations.     

Asthma and risk of lethal prostate cancer in the Health Professionals Follow‐Up Study

Inflammation, and more generally, the immune response are thought to influence the development of prostate cancer. To determine the components of the immune response that are potentially contributory, we prospectively evaluated the association of immune‐mediated conditions, asthma and hayfever, with lethal prostate cancer risk in the Health Professionals Follow‐up Study. We included 47,880 men aged 40–75 years with no prior cancer diagnosis. On the baseline questionnaire in 1986, the men reported diagnoses of asthma and hayfever and year of onset. On the follow‐up questionnaires, they reported new asthma and prostate cancer diagnoses. We used Cox proportional hazards regression to estimate relative risks (RRs). In total, 9.2% reported ever having been diagnosed with asthma. In all, 25.3% reported a hayfever diagnosis at baseline. During 995,176 person‐years of follow‐up by 2012, we confirmed 798 lethal prostate cancer cases (diagnosed with distant metastases, progressed to distant metastasis or died of prostate cancer [N = 625]). Ever having a diagnosis of asthma was inversely associated with risk of lethal (RR = 0.71, 95% confidence interval [CI] = 0.51–1.00) and fatal (RR = 0.64, 95% CI = 0.42–0.96) disease. Hayfever with onset in the distant past was possibly weakly positively associated with risk of lethal (RR = 1.10, 95% CI = 0.92–1.33) and fatal (RR = 1.12, 95% CI = 0.91–1.37) disease. Men who were ever diagnosed with asthma were less likely to develop lethal and fatal prostate cancer. Our findings may lead to testable hypotheses about specific immune profiles in the etiology of lethal prostate cancer.     

Sexually transmitted diseases and other urogenital conditions as risk factors for prostate cancer: a case–control study in Wayne County,Michigan

Objective To investigate associations between prostate cancer and sexually transmitted diseases (STDs), prostatitis, benign prostatic hyperplasia (BPH), and vasectomy in a population-based case–control study in Wayne County, Michigan, among African American and white men aged 50–74 years.Methods: Incident prostate cancer cases (n=700) from 1996–1998 were identified from the Metropolitan Detroit Cancer Surveillance System. Controls (n=604) were identified through random digit dialing and Medicare recipient lists, and frequency matched to cases on age and race. History of potential prostate cancer risk factors was ascertained through in-person interview.Results: Prostate cancer was not associated with STD or vasectomy history. History of prostatitis was associated with prostate cancer among all subjects (odds ratio [OR]=1.8, 95% confidence interval [CI]: 1.1, 2.9) and in African American men (OR=2.2, 95% CI: 1.1, 4.6). History of BPH was associated with prostate cancer among all subjects (OR=2.4, 95% CI: 1.8, 3.3); significant associations were observed in both African American (OR=2.7, 95% CI: 1.6, 4.4) and white (OR=2.3, 95% CI: 1.5, 3.4) men.Conclusions: Among all subjects, prostate cancer was associated with prostatitis and BPH history, but not with STD or vasectomy history. Prevention efforts could be enhanced if inflammatory or infectious etiologies are found to be of importance in the subsequent development of prostate cancer.     

Racial differences in clinical and pathological associations with PhIP-DNA adducts in prostate

African-American men have a higher dietary intake of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which is the most abundant heterocyclic amine in cooked meats and is carcinogenic in rat prostate through the formation of DNA adducts. To determine the clinical and demographic factors associated with PhIP-DNA adduct levels, the biologically effective dose of PhIP in human prostate, we immunohistochemically measured PhIP-DNA adducts in a study of 162 Caucasian and 102 African-American men who underwent radical prostatectomy for prostate cancer. A strong correlation between PhIP-DNA adduct levels in prostate tumor and adjacent non-tumor cells was observed (rho = 0.62; p < 0.0001); however, non-tumor cells had significantly higher adduct levels compared with tumor (0.167 optical density (OD) units +/- 0.043 vs. 0.104 OD +/- 0.027; p < 0.0001). Race was not associated with PhIP-DNA adduct levels in either tumor or non-tumor cells, but race-specific associations were observed. In prostate tumor and non-tumor cells, tumor volume had the strongest association with PhIP-DNA adducts in Caucasians, whereas in African-Americans prostate volume was most strongly associated with adduct levels in tumor cells and advanced Gleason grade had the strongest association in non-tumor cells. In race interaction models, while the only statistically significant interaction was between African-American race and advanced Gleason grade in non-tumor cells (beta = 0.029; p = 0.02), in tumor cells we observed opposite effects by race (positive for African-Americans, negative for Caucasians) for older age and high PSA levels at diagnosis. In conclusion, while PhIP-DNA adduct levels in prostate cells do not vary significantly by race, our results suggest that PhIP exposure may have stronger effects on prostate tumor differentiation in African-American men.     

Polycyclic aromatic hydrocarbon--DNA adducts in prostate and biochemical recurrence after prostatectomy.

PURPOSE: DNA adduct levels may be influenced by metabolic activity, DNA repair capabilities, and genomic integrity, all of which play a role in cancer progression. EXPERIMENTAL DESIGN: To determine if elevated DNA adducts are a marker for prostate cancer progression, we measured polycyclic aromatic hydrocarbon-DNA adducts by immunohistochemistry in prostate cells of 368 surgical prostate cancer patients treated at the Henry Ford Hospital in Detroit, Michigan, between September 1999 and July 2004. Patients were followed up to 5 years after surgery with relative risk for biochemical recurrence (BCR) estimated with a Cox proportional hazards model that adjusted for standard clinical risk factors. RESULTS: At 1 year of follow-up, patients with adduct levels above the median in tumor cells [hazard ratio (HR), 2.40; 95% confidence interval (95% CI), 1.10-5.27] and nontumor cells (HR, 3.22; 95% CI, 1.40-7.39) had significant increased risk of BCR, but these HRs decreased to 1.12 (95% CI, 0.68-1.83) and 1.46 (95% CI, 0.89-2.41) in tumor and nontumor cells at 5 years postsurgery. When we restricted our analysis to patients with advanced-stage (III+) disease, those with high adduct levels in either tumor (53.5% versus 30.2%; P = 0.07) or nontumor (55.2% versus 28.6%; P = 0.02) cells had BCR rates almost 2-fold higher. In race-stratified analyses, the greatest risk of BCR associated with high adduct levels (in nontumor cells) was for African American patients younger than 60 years old (HR, 3.79; 95% CI, 1.01-14.30). CONCLUSIONS: High polycyclic aromatic hydrocarbon-DNA adduct levels in nontumor prostate cells are most strongly associated with BCR between 1 and 2 years after surgery and in patient subsets defined by younger age, advanced tumor stage, and African American race.     

Prospective study of Type 2 diabetes mellitus,anti‐diabetic drugs and risk of prostate cancer

Type 2 diabetes mellitus (T2DM) has consistently been associated with decreased risk of prostate cancer; however, if this decrease is related to the use of anti‐diabetic drugs is unknown. We prospectively studied men in the comparison cohort in the Prostate Cancer data Base Sweden 3.0, with data on T2DM, use of metformin, sulfonylurea and insulin retrieved from national health care registers and demographic databases. Cox proportional hazards regression models were used to compute hazard ratios (HR) and 95% confidence intervals (CI) of prostate cancer, adjusted for confounders. The study consisted of 612,846 men, mean age 72 years (standard deviation; SD = 9 years), out of whom 25,882 men were diagnosed with prostate cancer during follow up, mean time of 5 years (SD = 3 years). Men with more than 1 year's duration of T2DM had a decreased risk of prostate cancer compared to men without T2DM (HR = 0.85, 95% CI = 0.82–0.88) but among men with T2DM, those on metformin had no decrease (HR = 0.96, 95% CI = 0.77–1.19), whereas men on insulin (89%) or sulfonylurea (11%) had a decreased risk (HR = 0.73, 95% CI = 0.55–0.98), compared to men with T2DM not on anti‐diabetic drugs. Men with less than 1 year's duration of T2DM had no decrease in prostate cancer risk (HR = 1.11, 95% CI = 0.95–1.31). Our results gave no support to the hypothesis that metformin protects against prostate cancer as recently proposed. However, our data gave some support to an inverse association between T2DM severity and prostate cancer risk.