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  • 1
    Keywords: CELL LUNG-CANCER ; RISK ; PROSTATE-CANCER ; COLON-CANCER ; CALCIUM ; PHYSICAL-ACTIVITY ; VITAMIN-D-RECEPTOR ; SERUM 25-HYDROXYVITAMIN-D ; 1,25-DIHYDROXYVITAMIN D-3 ; SUPPLEMENT USE
    Abstract: BACKGROUND: Individuals with higher blood 25-hydroxyvitamin D [25(OH)D] levels have a lower risk of developing colorectal cancer (CRC), but the influence of 25(OH)D on mortality after CRC diagnosis is unknown. METHODS: The association between prediagnostic 25(OH)D levels and CRC-specific (N = 444) and overall mortality (N = 541) was prospectively examined among 1,202 participants diagnosed with CRC between 1992 and 2003 in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Multivariable Cox proportional hazards models were used to calculate HRs and corresponding 95% CIs according to 25(OH)D quintiles and genetic variation within the VDR and CASR genes. Potential dietary, lifestyle, and metabolic effect modifiers were also investigated. RESULTS: There were 541 deaths, 444 (82%) due to CRC. Mean follow-up was 73 months. In multivariable analysis, higher 25(OH)D levels were associated with a statistically significant reduction in CRC-specific (P(trend) = 0.04) and overall mortality (P(trend) = 0.01). Participants with 25(OH)D levels in the highest quintile had an adjusted HR of 0.69 (95% CI: 0.50-0.93) for CRC-specific mortality and 0.67 (95% CI: 0.50-0.88) for overall mortality, compared with the lowest quintile. Except for a possible interaction by prediagnostic dietary calcium intake (P(interaction) = 0.01), no other potential modifying factors related to CRC survival were noted. The VDR (FokI and BsmI) and CASR (rs1801725) genotypes were not associated with survival. CONCLUSIONS: High prediagnostic 25(OH)D levels are associated with improved survival of patients with CRC. Impact: Our findings may stimulate further research directed at investigating the effects of blood vitamin D levels before, at, and after CRC diagnosis on outcomes in CRC patients. Cancer Epidemiol Biomarkers Prev; 21(4); 582-93. (c)2012 AACR.
    Type of Publication: Journal article published
    PubMed ID: 22278364
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  • 2
    Keywords: COHORT ; DISEASE ; DIFFERENTIATION ; PLASMA ; COLORECTAL-CANCER ; HUMAN GENOME ; REACTIVE OXYGEN METABOLITES ; ALL-CAUSE ; STRESS MARKERS ; NUCLEOREDOXIN
    Abstract: Long-lasting oxidative stress exposure may lead to relatively stable epigenetic modifications of the DNA in order to activate anti-oxidative defence mechanisms. Oxidative stress related DNA methylation may therefore be associated (causally or as a by-product) with cancer. We measured derivatives of reactive oxygen metabolites (D-ROM), total thiol levels (TTL) and DNA methylation with the Illumina Infinium 450K BeadChip in three samples of German individuals aged 〉/=50 years: n = 1,000 ESTHER study baseline participants (DNA methylation only), n = 99 ESTHER eight-year follow-up participants and n = 142 participants of the BLITZ study. The correlation coefficient of methylation at cg10342304 and D-ROM in the ESTHER 8-year follow-up sample (r = -0.427; P = 1 x 10(-5) ) was replicated with a P-value indicating statistical significance after correction for multiple testing in the BLITZ sample (r = -0.192; P = 0.022). The association was robust to adjusting for potential confounders. In the ESTHER baseline sample, the hazard ratio for cancer development in 11 years of follow-up comparing bottom and top quartile of DNA methylation at cg10342304 was 1.86 (95%-confidence-interval 1.01-3.43). In summary, this first epigenome-wide screening and replication study with oxidative status markers observed a negative correlation of D-ROM levels and DNA methylation at cg10342304 in two independent cohorts. This CpG site is located in the body region of the nucleoredoxin gene. The nucleoredoxin protein is a redox-dependent inhibitor of the Wnt/ss-catenin signaling pathway, a well-characterized cancer pathway. If the observed CpG-cancer association can be successfully replicated by other studies, this epigenetic marker could be an interesting biomarker of cancer risk. (c) 2015 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 26173806
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  • 3
    Abstract: BACKGROUND: Carotenoids and vitamin C are thought to be associated with reduced cancer risk because of their antioxidative capacity. OBJECTIVE: This study evaluated the associations of plasma carotenoid, retinol, tocopherol, and vitamin C concentrations and risk of breast cancer. DESIGN: In a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort, 1502 female incident breast cancer cases were included, with an oversampling of premenopausal (n = 582) and estrogen receptor-negative (ER-) cases (n = 462). Controls (n = 1502) were individually matched to cases by using incidence density sampling. Prediagnostic samples were analyzed for alpha-carotene, beta-carotene, lycopene, lutein, zeaxanthin, beta-cryptoxanthin, retinol, alpha-tocopherol, gamma-tocopherol, and vitamin C. Breast cancer risk was computed according to hormone receptor status and age at diagnosis (proxy for menopausal status) by using conditional logistic regression and was further stratified by smoking status, alcohol consumption, and body mass index (BMI). All statistical tests were 2-sided. RESULTS: In quintile 5 compared with quintile 1, alpha-carotene (OR: 0.61; 95% CI: 0.39, 0.98) and beta-carotene (OR: 0.41; 95% CI: 0.26, 0.65) were inversely associated with risk of ER- breast tumors. The other analytes were not statistically associated with ER- breast cancer. For estrogen receptor-positive (ER+) tumors, no statistically significant associations were found. The test for heterogeneity between ER- and ER+ tumors was statistically significant only for beta-carotene (P-heterogeneity = 0.03). A higher risk of breast cancer was found for retinol in relation to ER-/progesterone receptor-negative tumors (OR: 2.37; 95% CI: 1.20, 4.67; P-heterogeneity with ER+/progesterone receptor positive = 0.06). We observed no statistically significant interaction between smoking, alcohol, or BMI and all investigated plasma analytes (based on tertile distribution). CONCLUSION: Our results indicate that higher concentrations of plasma beta-carotene and alpha-carotene are associated with lower breast cancer risk of ER- tumors.
    Type of Publication: Journal article published
    PubMed ID: 26791185
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  • 4
    Keywords: COHORT ; colon ; HEALTH ; WOMEN ; POPULATIONS ; nutrition ; INFLAMMATORY MARKERS ; MENDELIAN RANDOMIZATION
    Abstract: High blood concentrations of C-reactive protein (CRP) have been associated with elevated risk of colorectal cancer in several prospective studies including the European Prospective Investigation into Cancer and Nutrition (EPIC), but it is unknown whether these observations reflect a causal relationship. We aimed to investigate whether CRP genetic variants associated with lifelong higher CRP concentrations translate into higher colorectal cancer risk. We conducted a prospective nested case-control study within EPIC including 727 cases diagnosed between 1992 and 2003 and 727 matched controls selected according to an incidence-density sampling protocol. Baseline CRP concentrations were measured in plasma samples by a high sensitivity assay. Tagging single nucleotide polymorphisms (SNPs) in the CRP gene (rs1205, rs1800947, rs1130864, rs2808630, rs3093077) were identified via HapMap. The causal effect of CRP on colorectal cancer risk was examined in a Mendelian Randomization approach utilizing multiple CRP genetic variants as instrumental variables. The SNPs rs1205, rs1800947, rs1130864 and rs3093077 were significantly associated with CRP concentrations and were incorporated in a CRP allele score which was associated with 13% higher CRP concentrations per allele count (95% confidence interval 8-19%). Using the CRP-score as instrumental variable, genetically twofold higher CRP concentrations were associated with higher risk of colorectal cancer (odds ratio 1.74, 95% confidence interval 1.06-2.85). Similar observations were made using alternative definitions of instrumental variables. Our findings give support to the hypothesis that elevated circulating CRP may play a direct role in the etiology of colorectal cancer.
    Type of Publication: Journal article published
    PubMed ID: 25043606
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  • 5
    Keywords: TRIALS
    Abstract: OBJECTIVE: To investigate the association between serum 25-hydroxyvitamin D concentrations (25(OH)D) and mortality in a large consortium of cohort studies paying particular attention to potential age, sex, season, and country differences. DESIGN: Meta-analysis of individual participant data of eight prospective cohort studies from Europe and the US. SETTING: General population. PARTICIPANTS: 26,018 men and women aged 50-79 years. MAIN OUTCOME MEASURES: All-cause, cardiovascular, and cancer mortality. RESULTS: 25(OH)D concentrations varied strongly by season (higher in summer), country (higher in US and northern Europe) and sex (higher in men), but no consistent trend with age was observed. During follow-up, 6695 study participants died, among whom 2624 died of cardiovascular diseases and 2227 died of cancer. For each cohort and analysis, 25(OH)D quintiles were defined with cohort and subgroup specific cut-off values. Comparing bottom versus top quintiles resulted in a pooled risk ratio of 1.57 (95% CI 1.36 to 1.81) for all-cause mortality. Risk ratios for cardiovascular mortality were similar in magnitude to that for all-cause mortality in subjects both with and without a history of cardiovascular disease at baseline. With respect to cancer mortality, an association was only observed among subjects with a history of cancer (risk ratio, 1.70 (1.00 to 2.88)). Analyses using all quintiles suggest curvilinear, inverse, dose-response curves for the aforementioned relationships. No strong age, sex, season, or country specific differences were detected. Heterogeneity was low in most meta-analyses. CONCLUSIONS: Despite levels of 25(OH)D strongly varying with country, sex, and season, the association between 25(OH)D level and all-cause and cause-specific mortality was remarkably consistent. Results from a long term randomised controlled trial addressing longevity are being awaited before vitamin D supplementation can be recommended in most individuals with low 25(OH)D levels.
    Type of Publication: Journal article published
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  • 6
    Keywords: RECEPTOR ; EXPRESSION ; TYROSINE KINASE ; EPIDEMIOLOGY ; colon ; nutrition ; RECTAL-CANCER ; INSULIN-RESISTANCE ; MENDELIAN RANDOMIZATION ; INSTRUMENTS
    Abstract: Fetuin-A, also referred to as alpha2-Heremans-Schmid glycoprotein (AHSG), is a liver protein known to inhibit insulin actions. Hyperinsulinemia is a possible risk factor for colorectal cancer; however, the role of fetuin-A in the development of colorectal cancer is unclear. We investigated the association between circulating fetuin-A and colorectal cancer risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Fetuin-A concentrations were measured in prediagnostic plasma samples from 1,367 colorectal cancer cases and 1,367 matched controls. In conditional logistic regression models adjusted for potential confounders, the estimated relative risk (95% confidence interval) of colorectal cancer per 40 microg/mL higher fetuin-A concentrations (approximately one standard deviation) was 1.13 (1.02-1.24) overall, 1.21 (1.05-1.39) in men, 1.06 (0.93-1.22) in women, 1.13 (1.00-1.27) for colon cancer and 1.12 (0.94-1.32) for rectal cancer. To improve causal inference in a Mendelian Randomization approach, five tagging single nucleotide polymorphisms of the AHSG gene were genotyped in a subset of 456 case-control pairs. The AHSG allele-score explained 21% of the interindividual variation in plasma fetuin-A concentrations. In instrumental variable analysis, genetically raised fetuin-A was not associated with colorectal cancer risk (relative risk per 40 microg/mL genetically determined higher fetuin-A was 0.98, 95% confidence interval: 0.73-1.33). The findings of our study indicate a modest linear association between fetuin-A concentrations and risk of colorectal cancer but suggest that fetuin-A may not be causally related to colorectal cancer development.
    Type of Publication: Journal article published
    PubMed ID: 25611809
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  • 7
    Keywords: NITRIC-OXIDE ; DNA ; CARCINOGENESIS ; DIETARY ; C-REACTIVE PROTEIN ; SERUM
    Abstract: Oxidative stress has been shown to play an important role in carcinogenesis, but prospective evidence for an association between biomarkers of oxidative stress and colorectal cancer (CRC) risk is limited. The authors investigated the association between prediagnostic serum levels of oxidative stress indicators (i.e., reactive oxygen metabolites (ROM) and ferric reducing ability of plasma (FRAP)) and CRC risk. This was examined in a nested case-control study (1,064 CRC cases, 1,064 matched controls) in the European Prospective Investigation Into Cancer and Nutrition cohort (1992-2003). Incidence rate ratios and 95% confidence intervals were calculated using conditional logistic regression analyses. ROM were associated with overall CRC risk (highest tertile vs. lowest: adjusted incidence rate ratio (IRR(adj)) = 1.91, 95% confidence interval (CI): 1.47, 2.48), proximal (IRR(adj) = 1.89, 95% CI: 1.06, 3.36) and distal (IRR(adj) = 2.31, 95% CI: 1.37, 3.89) colon cancer, and rectal cancer (IRR(adj) = 1.69, 95% CI: 1.05, 2.72). When results were stratified by tertile of follow-up time, the association remained significant only in participants with less than 2.63 years of follow-up (IRR(adj) = 2.28, 95% CI: 1.78, 2.94; P-heterogeneity 〈 0.01). FRAP was not associated with CRC risk. In conclusion, prediagnostic serum ROM levels were associated with increased risk of CRC. However, this association was seen only in subjects with relatively short follow-up, suggesting that the association results from production of reactive oxygen species by preclinical tumors.
    Type of Publication: Journal article published
    PubMed ID: 22422922
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  • 8
    Keywords: BLADDER-CANCER ; FRUIT ; antioxidants ; BETA-CAROTENE ; ALPHA-TOCOPHEROL ; RETINOL ; SERUM ; VEGETABLE CONSUMPTION ; CONTROLLED-TRIAL ; PHYSICIANS HEALTH
    Abstract: BACKGROUND: Published associations between dietary carotenoids and vitamin C and bladder cancer risk are inconsistent. Biomarkers may provide more accurate measures of nutrient status. OBJECTIVE: We investigated the association between plasma carotenoids and vitamin C and risk of urothelial cell carcinoma (UCC) in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition. DESIGN: A total of 856 patients with newly diagnosed UCC were matched with 856 cohort members by sex, age at baseline, study center, date and time of blood collection, and fasting status. Plasma carotenoids (alpha- and beta-carotene, beta-cryptoxanthin, lycopene, lutein, and zeaxanthin) were measured by using reverse-phase HPLC, and plasma vitamin C was measured by using a colorimetric assay. Incidence rate ratios (IRRs) were estimated by using conditional logistic regression with adjustment for smoking status, duration, and intensity. RESULTS: UCC risk decreased with higher concentrations of the sum of plasma carotenoids (IRR for the highest compared with the lowest quartile: 0.64; 95% CI: 0.44, 0.93; P-trend = 0.04). Plasma beta-carotene was inversely associated with aggressive UCC (IRR: 0.51; 95% CI: 0.30, 0.88; P-trend = 0.02). Plasma lutein was inversely associated with risk of nonaggressive UCC (IRR: 0.56; 95% CI: 0.32, 0.98; P-trend = 0.05). No association was observed between plasma vitamin C and risk of UCC. CONCLUSIONS: Although residual confounding by smoking or other factors cannot be excluded, higher concentrations of plasma carotenoids may reduce risk of UCC, in particular aggressive UCC. Plasma lutein may reduce risk of nonaggressive UCC.
    Type of Publication: Journal article published
    PubMed ID: 22952186
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