BACKGROUND Low levels of selenium have been associated with increased risk of prostate cancer (PCa). Selenoprotein P is the most abundant selenoprotein in serum and delivers ten selenocysteine residues to tissues. Variation in the selenoprotein P gene (SEPP1) may influence PCa development or modify the effects of selenium. We examined the association of SEPP1 single nucleotide polymorphisms (SNPs) with PCa risk and survival, and tested for interactions. METHODS The Physicians' Health Study (PHS) is a prospective cohort of 22,071 US physicians; we utilized a nested casecontrol study of 1,352 PCa cases and 1,382 controls. We assessed four SNPs capturing common variation within the SEPP1 locus. In a subset of men (n=80), we evaluated SEPP1 mRNA expression in tumors. RESULTS Two SNPs were significantly associated with PCa risk. For rs11959466, each T allele increased risk (odds ratio (OR)=1.31; 95% confidence interval (CI): 1.02,1.69; Ptrend=0.03). For rs13168440, the rare homozygote genotype decreased risk compared to the common homozygote (OR=0.56, 95% CI: 0.33, 0.96). Moreover, there was a significant interaction of rs13168440 with plasma selenium; increasing selenium levels were associated with decreased PCa risk only among men with the minor allele (Pinteraction=0.01). SEPP1 expression was significantly lower in men with lethal PCa than long-term survivors. CONCLUSIONS SEPP1 genetic variation was associated with PCa incidence; replication of these results in an independent dataset is necessary. These findings further support a causal link between selenium and PCa, and suggest that the effect of selenium may differ by genetics. Prostate 73: 700705, 2013. (c) 2012 Wiley Periodicals, Inc.

The aim of the study was to estimate the current prevalence of advanced cutaneous malignant melanoma in 2010 in the USA and to project prevalence estimates to the year 2015. An excel-based, multicohort natural disease history model was developed. It used incidence, recurrence, all-cause mortality, and US population data from the up-to-date surveillance, epidemiology, and end results program, the US census, and the literature. The prevalence was stratified by tumor stage, sex, and age. The model estimated that there were 800 735 malignant melanoma cases (258 per 100 000 individuals) in the USA in 2010, of which 10.4% were in advanced stages including stage III (22 per 100 000 individuals) and stage IV (four per 100 000 individuals). Among these advanced cases, 58.8% were men. In total, 42.1% of patients with advanced malignant melanoma were 65 years of age and older. Of these elderly patients with an advanced stage of the disease, 65.7% were men. The total number of cases and number of advanced cases were projected to increase from 2010 to 2015 by 24.4 and 21.0%, respectively. There will be approximately one million malignant melanoma cases (306 per 100 000 individuals) in the USA in 2015. The prevalence of advanced malignant melanoma is expected to increase in the next few years. Advanced malignant melanoma disproportionately affects men and the elderly in the USA.

It remains unknown whether increased risk with low levels of vitamin D is present for colon and/or rectal cancer. To investigate the association between circulating vitamin D levels and colon and rectal cancer, we examined the associations between plasma levels of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] and colon and rectal cancer in the Physicians' Health Study and then conducted a meta-analysis of eight prospective studies of circulating levels of 25(OH)D and colon and rectal cancers, including the Physicians' Health Study. Study-specific ORs and 95% CIs were pooled by using a random-effects model. A total of 1,822 colon and 868 rectal cancers were included in the meta-analysis. We observed a significant inverse association for colorectal cancer (OR = 0.66; 95% CI, 0.54–0.81), comparing top versus bottom quantiles of circulating 25(OH)D levels. The inverse association was stronger for rectal cancer (OR = 0.50 for top versus bottom quantiles; 95% CI, 0.28–0.88) than colon cancer (OR = 0.77; 95% CI, 0.56–1.07; P value for difference between colon and rectal cancer = 0.20). These data suggest an inverse association between circulating 25(OH)D levels and colorectal cancer, with a stronger association for rectal cancer. Cancer Prev Res; 4(5); 735–43. ©2011 AACR.

Abstract The role of selenium in prostate cancer (PCa) risk remains controversial, but many epidemiologic studies suggest an inverse association with more aggressive disease. A recently discovered selenoprotein, SEP15, which is highly expressed in the prostate, may play a role either independently or by modifying the effects of selenium. We genotyped four common single-nucleotide polymorphisms capturing common variation (frequency >5%; R2 > 0.8) within SEP15, as well as rs5859 in the 3′ untranslated region, previously reported to reduce the efficiency of selenium incorporation into SEP15. We examined the association of these single-nucleotide polymorphisms with PCa risk and PCa-specific mortality, as well as their interactions with plasma selenium levels, in the Physicians' Health Study. In this nested case-control study (1,286 cases and 1,267 controls), SEP15 polymorphisms were not significantly associated with PCa risk. However, among the cases, three variants were significantly associated with PCa-specific mortality [rs479341 hazard ratio (HR), 1.94; 95% confidence interval (95% CI), 1.15-3.25; rs1407131 HR, 2.85; 95% CI, 1.45-5.59; rs561104 HR, 1.54; 95% CI, 1.12-2.11] with a recessive model. Additionally, rs561104 significantly modified the association of plasma selenium with PCa survival (Pinteraction = 0.02); an inverse relationship of high levels of selenium with PCa mortality was apparent only among those without the increased risk genotype. This study provides evidence that SEP15 genetic variation may influence PCa mortality. Additionally, the association of selenium with PCa mortality was modified by a variant, suggesting the possibility that some men with PCa may benefit more from selenium than others, depending on their genotype. Cancer Prev Res; 3(5); 604–10. ©2010 AACR.

Abstract Background: Selenoprotein P (SelP) is the most common selenoprotein in serum and delivers selenium around the body, carrying up to ten selenocysteine residues per polypeptide. Antioxidants such as selenium may decrease the risk of developing prostate cancer (PCa). One study observed that serum SelP levels were lower in PCa cases than in controls while another found the expression of the gene, SEPP1, decreased with progression from normal prostate tissue to carcinoma to metastatic disease. Genetic variation in SEPP1 may also influence PCa risk or progression, or may modify the effects of selenium. We examined the association of single nucleotide polymorphisms (SNPs) in SEPP1 with PCa risk and survival, and tested for interactions with plasma selenium levels. Methods: The Physicians' Health Study (PHS) is a prospective cohort of 22,071 US physicians, of whom 2,584 were diagnosed with PCa between 1982 and 2005. Blood was collected from 68% of participants at baseline. We used a nested case-control study of 1,352 PCa cases and 1,382 controls matched on age, smoking status, and follow-up time; analyses were restricted to Caucasians. Using the HapMap database, we selected 5 SNPs to capture variation with a minor allele frequency >5% within SEPP1 and 5 kb up- and downstream. Four SNPs had high genotyping success (92–97%); the other failed genotyping, however, it tagged only itself so did not reduce the coverage. The incidence analysis used unconditional logistic regression, adjusting for matching factors. For survival analysis, individuals were censored at death or the end of follow-up; PCa deaths or metastases were considered lethal events (n=191). Plasma selenium levels were measured on 805 cases and 549 controls. Results: Two of the four SNPs were significantly associated with risk of incident PCa. For rs11959466, each additional T allele significantly increased the risk of PCa (odds ratio (OR)=1.31; 95% confidence interval (CI): 1.02, 1.69; ptrend=0.03), while for rs13168440, the minor allele homozygote genotype (CC) was associated with a decreased risk compared to the homozygote TT referent (OR=0.56, 95% CI: 0.33, 0.96). Moreover, there was a significant interaction of rs13168440 with quartiles of plasma selenium; increasing levels were associated with a decreased risk of PCa only among men with the minor allele (OR=0.76; 95% CI: 0.62, 0.93; pinteraction=0.02). None of the four SNPs was associated with PCa survival among the cases. Conclusions: Genetic variation within SEPP1 was associated with PCa incidence and may modify the association of selenium. Considering the multiple hypotheses tested, replication of these findings in an independent data set is needed to confirm or refute these results. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A122.

BACKGROUND Adipocytokines may mediate the association between adiposity and lethal prostate cancer outcomes. METHODS In the Physicians' Health Study, we prospectively examined the association of prediagnostic plasma concentrations of adiponectin and leptin with risk of developing incident prostate cancer (654 cases diagnosed 1982-2000 and 644 age-matched controls) and, among cases, risk of dying from prostate cancer by 2007. RESULTS Adiponectin concentrations were not associated with risk of overall prostate cancer. However, men with higher adiponectin concentrations had lower risk of developing high-grade or lethal cancer (metastatic or fatal disease). The relative risk (95% CI) comparing the highest quintile to the lowest (Q5 vs Q1) was 0.25 (95% CI 0.07-0.87; P(trend) = 0.02) for lethal cancer. Among all the cases, higher adiponectin concentrations predicted lower prostate cancer-specific mortality [hazard ratio (HR)(Q5 vs Q1)= 0.39; 95% CI 0.17-0.85; P(trend) = 0.02], independent of body mass index (BMI), plasma C-peptide (a marker of insulin secretion), leptin, clinical stage, and tumor grade. This inverse association was apparent mainly among men with a BMI >or=25 kg/m(2) (HR(Q5 vs Q1)= 0.10; 95% CI 0.01-0.78; P(trend) = 0.02), but not among men of normal weight (P(trend) = 0.51). Although the correlation of leptin concentrations with BMI (r = 0.58, P < 0.001) was stronger than that of adiponectin (r = -0.17, P < 0.001), leptin was unrelated to prostate cancer risk or mortality. CONCLUSIONS Higher prediagnostic adiponectin (but not leptin) concentrations predispose men to a lower risk of developing high-grade prostate cancer and a lower risk of subsequently dying from the cancer, suggesting a mechanistic link between obesity and poor prostate cancer outcome.

Background: The acid-labile subunit (ALS) acts in the insulin-like growth (IGF) system by binding circulating IGF-I in a ternary complex with binding protein (IGFBP)-3 to prevent IGF-I from crossing the endothelial barrier. Given the role of the IGF system in prostate cancer, ALS may influence carcinogenesis by modulating IGF-I levels or bioavailability. Methods: We undertook a prospective study nested in the Physicians' Health Study to examine ALS, free IGF-I, and prostate cancer. We assayed circulating levels of ALS and IGF components among 545 incident cases and 545 matched controls. We calculated relative risks (RR) and 95% confidence intervals (95% CI) adjusted for life-style factors, total IGF-I, and IGFBP3. Results: ALS was positively correlated with total IGF-I (r = 0.58), IGFBP3 (r = 0.68), and free IGF-I (r = 0.36). Comparing highest versus lowest quartiles, we found no association between free IGF-I and prostate cancer risk (RR, 0.9; 95% CI, 0.6-1.3). In contrast, ALS was positively associated with risk among men in the 2nd (RR, 1.5; 94% CI, 1.0-2.3), 3rd (RR, 1.6; 94% CI, 1.1-2.5), and 4th quartiles (RR, 1.4; 94% CI, 0.9-2.1) compared with lowest quartile. The association was stronger for advanced stage tumors (RR, 2.0; 94% CI, 0.8-4.6). There was a suggestion of an interaction between ALS and total IGF-I, whereby high circulating IGF-I was associated with an increased risk of advanced prostate cancer among men with low but not higher ALS levels. Discussion: Plasma ALS is positively associated with prostate cancer risk, and may interact biologically with IGF-I to affect carcinogenesis. These data provide further support for the role of the IGF axis in prostate cancer. Cancer Epidemiol Biomarkers Prev; 19(2); 484–91

Endostatin inhibits endothelial cell proliferation and migration, prerequisites of angiogenesis. A functional missense mutation ( D104N ) in endostatin was associated with an increased prostate cancer risk in a small study. We undertook a larger, prospective study within the Physicians' Health Study to examine D104N and prostate cancer risk and progression among 544 incident prostate cancer cases (1982–1995) and 678 matched controls. The association between endostatin genotype and cancer risk was estimated using logistic regression models. Among cases, Cox models were used to assess D104N and lethal prostate cancer. Given the role of endostatin in neovascularization of adipose tissue, we cross classified individuals on D104N genotype and body mass index (BMI). The genotype frequency was 1.3% homozygous (NN), 14.5% heterozygous (DN) and 84.2% wildtype homozygous (DD). There was no overall association between carriage of the N allele and prostate cancer risk (RR = 1.2, 95% CI: 0.9–1.6) or cancer‐specific mortality (HR = 1.2, 0.7–1.8). Cases with the polymorphic allele were less likely to be overweight (BMI 25 kg/m 2 or greater, 26%) compared to men wildtype homozygous (48%), p < 0.0001. Being overweight was associated with a 60% greater prostate cancer risk among those who were wildtype homozygous. In contrast, being overweight was associated with a 50% lower risk of cancer among those with the N allele. We did not confirm an earlier observation between the D104N polymorphism and prostate cancer. However, our data indicate that prostate cancer cases who carry the variant N allele are more likely to be overweight, and may be more susceptible to the angiogenic influences of obesity in prostate cancer pathogenesis. © 2009 UICC

Vitamin B6 may lower risk of colorectal cancer by preventing aberrations in one-carbon metabolism or by anti-inflammatory effects. We prospectively evaluated the association between plasma levels of pyridoxal 5′-phosphate (PLP; the active form of vitamin B6) and risk of colorectal cancer in a nested case-control study within the Physicians' Health Study. Among 14,916 men who provided blood specimens in 1982 to 1984, we identified 197 incident colorectal cancer cases through 2000 and individually matched them to 371 controls by age and smoking status. Plasma PLP levels were positively correlated with cold cereal intake and plasma levels of folate and vitamin B12 (age- and smoking-adjusted partial correction r = 0.28-0.48) and slightly inversely correlated with body mass index (r = −0.11) and plasma levels of homocysteine, C-reactive protein, tumor necrosis factor-α receptor 2, and interleukin-6 (r = −0.23 to −0.14). With control for these factors and known risk factors for colorectal cancer, plasma PLP levels were significantly inversely associated with risk of colorectal cancer; compared with men in the lowest quartile, those with PLP in quartiles 2 to 4 had relative risks (95% confidence interval) of 0.92 (0.55-1.56), 0.42 (0.23-0.75), and 0.49 (0.26-0.92; Ptrend = 0.01), respectively. In conclusion, vitamin B6 may protect against colorectal cancer independent of other one-carbon metabolites and inflammatory biomarkers. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1197–202)

Interleukin-6 (IL-6) and C-reactive protein (CRP) are elevated in prostate cancer patients, but the role of prediagnostic levels of these inflammatory mediators on prostate cancer outcomes is unclear. We undertook a large, prospective case-control study to evaluate the relation between prediagnostic levels of IL-6 and CRP and prostate cancer incidence and mortality. We also investigated the role of the IL-6 (-174 G/C) polymorphism in relation to circulating levels of IL-6 and CRP, as well as cancer risk and mortality. We used unconditional logistic regression that adjusted for matching factors to analyze prostate cancer risk. For analyses of prostate cancer mortality, we conducted survival analyses in cases. Because of the strong link between inflammatory markers and body mass index (BMI), we assessed interactions between BMI and plasma levels on prostate cancer outcomes. Neither IL-6 nor CRP plasma levels varied significantly by IL-6 genotype. Genotype was not associated with prostate cancer risk or survival. Though neither IL-6 nor CRP was associated with prostate cancer incidence overall, we observed a statistically significant interaction between IL-6 and BMI on prostate cancer incidence (p(interaction) < 0.01). Increasing IL-6 levels were positively associated with risk in healthy weight men, but inversely associated with risk in over-weight men. Further, prediagnostic IL-6 was associated with time to prostate cancer progression/death among healthy weight prostate cancer cases (p(trend) = 0.02). Adjusted hazard ratios were 1.73 (95% CI: 0.86, 3.51) comparing the highest to lowest IL-6 level. Our study suggests that IL-6 may potentially be involved in the development or progression of prostate cancer. (C) 2008 Wiley-Liss, Inc.

Abstract A109 Growing evidence suggests an elevated risk of colorectal cancer among individuals with low levels of vitamin D, the biological actions of which is mediated by the vitamin D receptor (VDR). We examined the prospective associations between three VDR single nucleotide polymorphisms (SNPs) (BsmI (bb, bB/BB), FokI (FF, Ff/ff), and Cdx2 (G>A)) and colorectal cancer risk and their interactions with plasma vitamin D status in a nested case-control study among men in the Physicians’ Health Study. A total of 249 incident colorectal cancer cases were identified through 2000 among men who provided blood specimens in 1982-1984 and individually matched to controls by age and smoking. We used conditional logistic regression to calculate the relative risk (RR) and 95% confidence interval (95% CI). We found that men with the VDR Cdx2 variant A allele tended to have a lower risk of developing colorectal cancer compared to men with the homozygous GG genotype (RR=0.71; 95% CI = 0.50-1.02; P = 0.06). Moreover, the lower risk of colorectal cancer associated with the VDR Cdx2 A genotype was mainly confined to men with low vitamin D status (plasma 25(OH)D below median level; RR = 0.45; 95% CI = 0.24-0.84; P = 0.03) but not among men with vitamin D levels above the median (P for interaction = 0.04). We found no statistically significant associations for the other two VDR SNPs, FokI or BsmI, or statistically significant interactions between plasma 25(OH)D levels and these two SNPs. Our prospective data suggest the hypothesis that the functional polymorphic Cdx2 A allele variation in the VDR gene, which is linked to a higher transcriptional activity of the VDR, may be protective against colorectal cancer development when vitamin D status is low. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A109.

Background Excess body-mass index (BMI) has been associated with adverse outcomes in prostate cancer, and hyperinsulinaemia is a candidate mediator, but prospective data are sparse. We assessed the effect of prediagnostic BMI and plasma C-peptide concentration (reflecting insulin secretion) on prostate cancer-specific mortality after diagnosis.Methods This study involved men diagnosed with prostate cancer during the 24 years of follow-up in the Physicians' Health Study. BMI measurements were available at baseline in 1982 and eight years later in 1990 for 2546 men who developed prostate cancer. Baseline C-peptide concentration was available in 827 men. We used Cox proportional hazards regression models controlling for age, smoking, time between BMI measurement and prostate cancer diagnosis, and competing causes of death to assess the risk of prostate cancer-specific mortality according to BMI and C-peptide concentration.Findings Of the 2546 men diagnosed with prostate cancer during the follow-up period, 989 (38.8%) were overweight (BMI 25.0-29.9 kg/m(2)) and 87 (3.4%) were obese (BMI >= 30 kg/m(2)). 281 men (11%) died from prostate cancer during this follow-up period. Compared with men of a healthy weight (BMI <25 kg/m(2)) at baseline, overweight men and obese men had a significantly higher risk of prostate cancer mortality (proportional hazard ratio [HR] 1.47 [95% CI 1.16-1-88] for overweight men and 2.66 [1.62-4.39] for obese men; p(trend)<0.0001). The trend remained significant after controlling for clinical stage and Gleason grade and was stronger for prostate cancer diagnosed during the PSA screening era (1991-2007) compared with during the pre-PSA screening era (1982-1990) or when using BMI measurements obtained in 1990 compared with those obtained in 1982. Of the 827 men with data available for baseline C-peptide concentration, 117 (14%) died from prostate cancer. Men with C-peptide concentrations in the highest quartile (high) versus the lowest quartile (low) had a higher risk of prostate cancer mortality (HR 2.38 [95% CI 1.31-4.30]; p(trend)=0.008). Compared with men with a BMI less than 25 kg/m(2) and low C-peptide concentrations, those with a BMI of 25 kg/m(2) or more and high C-peptide concentrations had a four-times higher risk of mortality (4.12 [1.97-8.61]; p(interaction)=0.001) independent of clinical predictors.Interpretation Excess bodyweight and a high plasma concentration of C-peptide both predispose men with a subsequent diagnosis of prostate cancer to an increased likelihood of dying of their disease. Patients with both factors have the worst outcome. Further studies are now needed to confirm these findings.

BACKGROUNDVitamin D insufficiency is a common public health problem nationwide. Circulating 25-hydroxyvitamin D3 (25[OH]D), the most commonly used index of vitamin D status, is converted to the active hormone 1,25 dihydroxyvitamin D3 (1,25[OH]2D), which, operating through the vitamin D receptor (VDR), inhibits in vitro cell proliferation, induces differentiation and apoptosis, and may protect against prostate cancer. Despite intriguing results from laboratory studies, previous epidemiological studies showed inconsistent associations of circulating levels of 25(OH)D, 1,25(OH)2D, and several VDR polymorphisms with prostate cancer risk. Few studies have explored the joint association of circulating vitamin D levels with VDR polymorphisms.METHODS AND FINDINGSDuring 18 y of follow-up of 14,916 men initially free of diagnosed cancer, we identified 1,066 men with incident prostate cancer (including 496 with aggressive disease, defined as stage C or D, Gleason 7-10, metastatic, and fatal prostate cancer) and 1,618 cancer-free, age- and smoking-matched control participants in the Physicians' Health Study. We examined the associations of prediagnostic plasma levels of 25(OH)D and 1,25(OH)2D, individually and jointly, with total and aggressive disease, and explored whether relations between vitamin D metabolites and prostate cancer were modified by the functional VDR FokI polymorphism, using conditional logistic regression. Among these US physicians, the median plasma 25(OH)D levels were 25 ng/ml in the blood samples collected during the winter or spring and 32 ng/ml in samples collected during the summer or fall. Nearly 13% (summer/fall) to 36% (winter/spring) of the control participants were deficient in 25(OH)D (<20 ng/ml) and 51% (summer/fall) and 77% (winter/spring) had insufficient plasma 25(OH)D levels (<32 ng/ml). Plasma levels of 1,25(OH)2D did not vary by season. Men whose levels for both 25(OH)D and 1,25(OH)2D were below (versus above) the median had a significantly increased risk of aggressive prostate cancer (odds ratio [OR] = 2.1, 95% confidence interval [CI] 1.2-3.4), although the interaction between the two vitamin D metabolites was not statistically significant (pinteraction = 0.23). We observed a significant interaction between circulating 25(OH)D levels and the VDR FokI genotype (pinteraction < 0.05). Compared with those with plasma 25(OH)D levels above the median and with the FokI FF or Ff genotype, men who had low 25(OH)D levels and the less functional FokI ff genotype had increased risks of total (OR = 1.9, 95% CI 1.1-3.3) and aggressive prostate cancer (OR = 2.5, 95% CI 1.1-5.8). Among men with plasma 25(OH)D levels above the median, the ff genotype was no longer associated with risk. Conversely, among men with the ff genotype, high plasma 25(OH)D level (above versus below the median) was related to significant 60% approximately 70% lower risks of total and aggressive prostate cancer.CONCLUSIONSOur data suggest that a large proportion of the US men had suboptimal vitamin D status (especially during the winter/spring season), and both 25(OH)D and 1,25(OH)2D may play an important role in preventing prostate cancer progression. Moreover, vitamin D status, measured by 25(OH)D in plasma, interacts with the VDR FokI polymorphism and modifies prostate cancer risk. Men with the less functional FokI ff genotype (14% in the European-descent population of this cohort) are more susceptible to this cancer in the presence of low 25(OH)D status.

Background: Animal models suggest that n-3 fatty acids inhibit prostate cancer proliferation, whereas n-6 fatty acids promote it, but epidemiologic studies do not uniformly support these findings.Methods: A nested case-control study was conducted among 14,916 apparently healthy men who provided blood samples in 1982. Blood fatty acid levels were determined for 476 men diagnosed with prostate cancer during a 13-year follow-up and their matched controls. Conditional logistic regression was used to estimate the relative risks (RR) and 95% confidence intervals (95% CD of total, non-aggressive (stage A/B and Gleason < 7) and aggressive (stage C/D, Gleason 7, subsequent distant metastasis or death) prostate cancer associated with blood levels of specific fatty acids expressed as percentages of total fatty acids.Results: Whole blood levels of all long-chain n-3 fatty acids examined and of linoleic acid were inversely related to overall prostate cancer risk (RRQ5vs.Q1, 0-59; 95% CI, 0.38-0.93; P-trend = 0.01 for total long-chain n-3 fatty acids and RRQ5vs.Q1 0.62; 95% CI, 0.41-0.95; P-trend = 0.03 for linoleic). Blood levels of gamma-linolenic and dihomo-gamma-linolenic acids, fatty acids resulting from the metabolism of linoleic acid, were directly associated with prostate cancer (RR, 1.41; 95% CI, 0.94-2.12; Ptrend = 0.05 for gamma-linolenic and RR, 1.54; 95% CI, 1.03-2.30; P-trend = 0.02 for dihomo-gamma-linolenic acid). Levels of arachidonic and ct-linolenic acids were unrelated to prostate cancer.Conclusions: Higher blood levels of long-chain n-3 fatty acids, mainly found in marine foods, and of linoleic acid, mainly found in non-hydrogenated vegetable oils, are associated with a reduced risk of prostate cancer. The direct associations of linoleic acid metabolites with prostate cancer risk deserve further investigation.

Background: Experimental evidence has suggested that estrogen receptor α (coded by the gene ESR1) might increase prostate cancer risk, whereas estrogen receptor β (coded by the gene ESR2) might reduce prostate cancer risk. Methods: We investigated the relationship with prostate cancer risk of both a TA repeat polymorphism in the ESR1 5′ region, ESR1 (TA)n, and with a CA repeat polymorphism in intron 5 of ESR2, ESR2 (CA)n, in a case-control study (545 cases and 674 controls) nested in the Physicians' Health Study. Results: Prostate cancer risk was highest for carriers of ESR1 (TA)24 and ESR1 (TA)25. Replacing one modal ESR1 (TA)14 allele with one ESR1 (TA)24 allele yielded an odds ratio of 1.42 (95% confidence interval, 1.00-2.00; P = 0.05). Replacing one ESR1 (TA)14 allele with one ESR1 (TA)25 allele yielded an odds ratio of 2.10 (95% confidence interval, 1.15-3.84; P = 0.02). ESR2 (CA)n showed no effects on prostate cancer risk. Conclusions: The ESR1 (TA)n polymorphism might play a role in prostate cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2233–6)

Distinguishing aggressive prostate cancer from indolent disease represents an important clinical challenge, because current therapy may lead to overtreatment of men with limited disease. The prostate-specific membrane antigen (PSMA) is a membrane-bound glycoprotein that is highly restricted to the prostate. Previously, studies analyzing the expression of PSMA have found an up-regulation in correlation with prostate cancer, particularly in advanced cancer. This association is ideal for an application as a prognostic marker. In the current study, we characterized PSMA expression in a high-risk cohort and evaluated its potential use as predictive marker of prostate-specific antigen (PSA) recurrence. PSMA expression was analyzed by immunohistochemistry using tissue microarrays composed of tumor samples from 450 patients. Protein intensity was recorded using a semiautomated quantitative microscope system (ACIS II; Clarient Chromavision Medical Systems, San Juan Capistrano, CA). PSMA expression levels differed significantly (P < .001) between benign prostatic tissue, localized prostate cancer, and lymph node metastases. Dividing the cohort into high- and low-PSMA expressing cancers based on the median area of positive staining, we found that high PSMA levels were associated with significant increase of PSA recurrence (P = .004). This was independent of clinical parameters such as lymph node tumor burden (lymph node density, >20%; P < .001), extraprostatic extension (P = .017), seminal vesicle invasion (P < .001), and high Gleason score (8-10, P = .006). In a multivariate model, PSMA expression and metastases to pelvic lymph nodes were significantly associated with time to PSA recurrence (HR, 1.4; 95% confidence interval, 1.1-2.8, P = .017; and hazard ratio, 5; 95% confidence interval, 2.6-9.7, P < .001, respectively). In summary, PSMA is independently associated with PSA recurrence in a high-risk cohort and thus might provide insight into the additional use of adjuvant therapy. Validation on other cohorts is required.

BACKGROUND:The Hypoxia-inducible factor-1 (HIF-1) plays an important role in regulating angiogenesis in response to hypoxia. Two non-synonymous polymorphisms (P582S C-->T and A588T G-->A) in the coding region of the subunit 1alpha (HIF-1alpha) gene have been associated with enhanced stability of the protein and androgen-independent prostate cancer (CaP). Insulin-like growth factor binding protein (IGFBP)-3 mRNA is more abundantly expressed in hypoxia-related inflammatory angiogenesis and recent in vivo data suggest that IGFBP-3 has direct, IGF-independent inhibitory effects on angiogenesis.METHODS:We examined the association of these polymorphisms with CaP among 1,072 incident cases and 1,271 controls, and further explored their joint associations with various prediagnostic plasma vascular endothelial growth factor (VEGF), IGF-I, and IGFBP-3 levels.RESULTS:Neither the P582S nor the A588T polymorphism was associated with risk of overall or metastatic/fatal CaP. However, we found that, among men with the homozygous CC wild-type (but not CT/TT) of the HIF-1alpha P582S, higher IGFBP-3 levels (>/= vs. <median) were associated with a 28% (95% CI, 0.55-0.95; P(interaction) = 0.01) lower risk of overall CaP and a 53% (0.25-0.88; P(interaction) = 0.11) lower risk of metastatic and fatal CaP. The A588T polymorphism was too rare to assess interactions.CONCLUSIONS:The two HIF-1alpha gene polymorphisms were not directly associated with CaP, but the interaction between the P582S polymorphism and IGFBP-3 merits further evaluation in mechanistic studies.

A199 A prospective study of plasma adiponectin levels and prostate cancer risk and survival ABSTRACT Background: Obesity/Overweight is associated with metastatic and fatal prostate cancer and predicts poor survival; it thus may play a significant role in cancer progression. Adiponectin is an adipocyte-derived cytokine, and its circulating levels are inversely correlated with adiposity. At physiological concentrations, adiponectin inhibits in vitro cell growth of both the androgen-dependent and androgen-independent prostate cancer cell lines, and might therefore be beneficial. However, human data is very sparse. Methods: In the Physicians9 Health Study, after excluding men who reported diabetes at the baseline, 610 cases and 583 age-matched controls were available for the analyses. We examined the associations of prediagnostic plasma adiponectin levels with prostate cancer incidence among 583 case-control pairs (1:1), using conditional logistic regression. Of these cases, 194 men had high-grade (Gleason 7-10 or poorly differentiated) tumor and 117 men had lethal disease, defined as stage D at diagnosis, or developed metastases or died of prostate cancer during the follow-up by 2005. We further applied Cox proportional hazards models to assess the role of adiponectin in prostate cancer survival among 610 cases. Results: Adiponectin levels were inversely correlated with baseline body mass index (BMI, correlation coefficient, r = -0.18, P

: NKX3.1 is a prostate-specific homeobox gene that maps to chromosome 8p21, the most frequent target for loss of heterozygosity in prostate cancer. NKX3.1 is a haploinsufficient tumor suppressor in the prostate. We found that IGFBP-3expreession was activated 10-fold by NKX3.1 in cell lines and tissues. IGFBP-3 is an inhibitor of IGF-1, a serum component that when elevated is a risk factor for prostate cancer. NKX3.1 expression inhibits IGFIR signaling and diminishes IRS-1 phosphorylation. Knock down of IGFBP-3 attenuates the growth suppressive effects of NKX3.1. NKX3.1 C154T is a polymorphic allele present in ~10% of the population. The polymorphic allele codes for a variant protein that replaces arginine 52 with cysteine. NXK3.1 C154T confers a minimally increased risk for prostatic enlargement and for prostate cancer. In a cohort of cases and controls with known NKX3.1 genotype we found that the effect of serum IGF-1 on prostate cancer risk was seen only in men with at least one polymorphic NKX3.1 allele. Consistent with its apparent interaction with IGF-1 in prostate cancer risk, NKX3.1 R52C protein is attenuated in activation of IGFBP-3. The data therefore show that the two prostate cancer risk factors, NKX3.1 R52C and circulating IGF-1 interact. NKX3.1 R52C activates less IGFBP-3 expression than its wild type counterpart and thereby predisposes prostate epithelial cells to the proliferative and antiapoptotic effects of IGF-1, increasing the risk for prostate cancer.

Objectives To characterize lymph node metastasis of prostate cancer (PCa) and identify the parameters associated with patient outcome. The incidence of clinically localized PCa with concurrent lymph node metastasis has decreased to less than 1% in the United States but is between 10% and 15% in other countries. Methods Our study cohort of 1148 patients underwent radical prostatectomy in Ulm, Germany, between 1986 and 2002, and 201 (18%) had lymph node-positive PCa. Results The metastases showed growth architecture resembling primary PCa. We assigned a Gleason pattern and evaluated for size, extranodal extension, and lymphovascular invasion (LVI). Of 201 patients, 155 had original pathology slides available; 36 of the 155 were excluded because of preoperative hormonal ablation therapy. Of the remaining 119 patients, 22 (19%) were assigned Gleason pattern 3, 93 (78%) Gleason pattern 4, and 4 (3%) Gleason pattern 5. Extranodal extension was present in 66 (55%) of 119 patients and LVI in 29 (25%). An increased risk of prostate-specific antigen (PSA) recurrence was found for Gleason pattern 4/5 (hazard ratio [HR] 2.5, P = 0.038), LVI in the lymph nodes (HR 1.9, P = 0.038), and nuclear grade of the primary tumor (HR 2, P = 0.025). Independent predictors of PSA recurrence included LVI and nuclear grade (HR 1.9, P = 0.03 and HR 2, P = 0.03, respectively). Conclusions Lymph node metastases of PCa are heterogeneous and have a close relation to the corresponding primary tumor. Most patients with lymph node-positive PCa remained disease free for up to 13 years after radical prostatectomy. Independent predictors of PSA recurrence among those with lymph node-positive PCa included LVI in the lymph nodes and the nuclear grade of the primary tumor. These parameters may be useful in predicting PSA recurrence in lymph node-positive PCa and could be included in patient follow-up.