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2014

Dietary vitamin D intake and risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition: the EPIC-InterAct study

Abbas S., Linseisen J., Rohrmann S., Beulens J.W., Buijsse B., Amiano P., Ardanaz E., Balkau B., Boeing H., Clavel-Chapelon F., Fagherazzi G., Franks P.W., Gavrila D., Grioni S., Kaaks R., Key T.J., Khaw K.T., Kuhn T., Mattiello A., Molina-Montes E., Nilsson P.M., Overvad K., Quiros J.R., Rolandsson O., Sacerdote C., Saieva C., Slimani N., Sluijs I., Spijkerman A.M., Tjonneland A., Tumino R., van der A.DL, Zamora-Ros R., Sharp S.J., Langenberg C., Forouhi N.G., Riboli E., Wareham N.J.

Eur J Clin Nutr; 2014; 68(2): 196-202

Abstract as provided by PubMed

Background/Objectives:Prospective cohort studies have indicated that serum vitamin D levels are inversely related to risk of type 2 diabetes. However, such studies cannot determine the source of vitamin D. Therefore, we examined the association of dietary vitamin D intake with incident type 2 diabetes within the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study in a heterogeneous European population including eight countries with large geographical variation.Subjects/Methods:Using a case-cohort design, 11 245 incident cases of type 2 diabetes and a representative subcohort (N=15 798) were included in the analyses. Hazard ratios (HR) and 95% confidence intervals (CIs) for type 2 diabetes were calculated using a Prentice-weighted Cox regression adjusted for potential confounders. Twenty-four-hour diet-recall data from a subsample (N=2347) were used to calibrate habitual intake data derived from dietary questionnaires.Results:Median follow-up time was 10.8 years. Dietary vitamin D intake was not significantly associated with the risk of type 2 diabetes. HR and 95% CIs for the highest compared to the lowest quintile of uncalibrated vitamin D intake was 1.09 (0.97-1.22) (Ptrend=0.17). No associations were observed in a sex-specific analysis. The overall pooled effect (HR (95% CI)) using the continuous calibrated variable was 1.00 (0.97-1.03) per increase of 1 mug/day dietary vitamin D.Conclusions:This observational study does not support an association between higher dietary vitamin D intake and type 2 diabetes incidence. This result has to be interpreted in light of the limited contribution of dietary vitamin D on the overall vitamin D status of a person

Combined impact of healthy lifestyle factors on colorectal cancer: a large European cohort study

Aleksandrova K., Pischon T., Jenab M., Bueno-De-Mesquita H., Fedirko V., Norat T., Romaguera D., Knuppel S., Boutron-Ruault M.C., Dossus L., Dartois L., Kaaks R., Li K., Tjonneland A., Overvad K., Quiros J., Buckland G., Sanchez M., Dorronsoro M., Chirlaque M.D., Barricarte A., Khaw K.T., Wareham N.J., Bradbury K.E., Trichopoulou A., Lagiou P., Trichopoulos D., Palli D., Krogh V., Tumino R., Naccarati A., Panico S., Siersema P.D., Peeters P., Ljuslinder I., Johansson I., Ericson U., Ohlsson B., Weiderpass E., Skeie G., Borch K., Rinaldi S., Romieu I., Kong J., Gunter M.J., Ward H.A., Riboli E., Boeing H.

BMC Med; 2014; 12(1): 168

Abstract as provided by PubMed

BACKGROUND: Excess body weight, physical activity, smoking, alcohol consumption and certain dietary factors are individually related to colorectal cancer (CRC) risk; however, little is known about their joint effects. The aim of this study was to develop a healthy lifestyle index (HLI) composed of five potentially modifiable lifestyle factors - healthy weight, physical activity, non-smoking, limited alcohol consumption and a healthy diet, and to explore the association of this index with CRC incidence using data collected within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: In the EPIC cohort, a total of 347,237 men and women, 25- to 70-years old, provided dietary and lifestyle information at study baseline (1992 to 2000). Over a median follow-up time of 12 years, 3,759 incident CRC cases were identified. The association between a HLI and CRC risk was evaluated using Cox proportional hazards regression models and population attributable risks (PARs) have been calculated. RESULTS: After accounting for study centre, age, sex and education, compared with 0 or 1 healthy lifestyle factors, the hazard ratio (HR) for CRC was 0.87 (95% confidence interval (CI): 0.44 to 0.77) for two factors, 0.79 (95% CI: 0.70 to 0.89) for three factors, 0.66 (95% CI: 0.58 to 0.75) for four factors and 0.63 (95% CI: 0.54 to 0.74) for five factors; P-trend <0.0001. The associations were present for both colon and rectal cancers, HRs, 0.61 (95% CI: 0.50 to 0.74; P for trend <0.0001) for colon cancer and 0.68 (95% CI: 0.53 to 0.88; P-trend <0.0001) for rectal cancer, respectively (P-difference by cancer sub-site = 0.10). Overall, 16% of the new CRC cases (22% in men and 11% in women) were attributable to not adhering to a combination of all five healthy lifestyle behaviours included in the index. CONCLUSIONS: Combined lifestyle factors are associated with a lower incidence of CRC in European populations characterized by western lifestyles. Prevention strategies considering complex targeting of multiple lifestyle factors may provide practical means for improved CRC prevention

Biomarker patterns of inflammatory and metabolic pathways are associated with risk of colorectal cancer: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)

Aleksandrova K., Jenab M., Bueno-de-Mesquita H.B., Fedirko V., Kaaks R., Lukanova A., van Duijnhoven F.J., Jansen E., Rinaldi S., Romieu I., Ferrari P., Murphy N., Gunter M.J., Riboli E., Westhpal S., Overvad K., Tjonneland A., Halkjaer J., Boutron-Ruault M.C., Dossus L., Racine A., Trichopoulou A., Bamia C., Orfanos P., Agnoli C., Palli D., Panico S., Tumino R., Vineis P., Peeters P.H., Duell E.J., Molina-Montes E., Quiros J.R., Dorronsoro M., Chirlaque M.D., Barricarte A., Ljuslinder I., Palmqvist R., Travis R.C., Khaw K.T., Wareham N., Pischon T., Boeing H.

Eur J Epidemiol; 2014; 29(4): 261-275

Abstract as provided by PubMed

A number of biomarkers of inflammatory and metabolic pathways are individually related to higher risk of colorectal cancer (CRC); however, the association between biomarker patterns and CRC incidence has not been previously evaluated. Our study investigates the association of biomarker patterns with CRC in a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC). During median follow-up time of 7.0 (3.7-9.4) years, 1,260 incident CRC cases occurred and were matched to 1,260 controls using risk-set sampling. Pre-diagnostic measurements of C-peptide, glycated hemoglobin, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), reactive oxygen metabolites (ROM), insulin-like growth factor 1, adiponectin, leptin and soluble leptin receptor (sOB-R) were used to derive biomarker patterns from principal component analysis (PCA). The relation with CRC incidence was assessed using conditional logistic regression models. We identified four biomarker patterns 'HDL-C/Adiponectin fractions', 'ROM/CRP', 'TG/C-peptide' and 'leptin/sOB-R' to explain 60 % of the overall biomarker variance. In multivariable-adjusted logistic regression, the 'HDL-C/Adiponectin fractions', 'ROM/CRP' and 'leptin/sOB-R' patterns were associated with CRC risk [for the highest quartile vs the lowest, incidence rate ratio (IRR) = 0.69, 95 % CI 0.51-0.93, P-trend = 0.01; IRR = 1.70, 95 % CI 1.30-2.23, P-trend = 0.002; and IRR = 0.79, 95 % CI 0.58-1.07; P-trend = 0.05, respectively]. In contrast, the 'TG/C-peptide' pattern was not associated with CRC risk (IRR = 0.75, 95 % CI 0.56-1.00, P-trend = 0.24). After cases within the first 2 follow-up years were excluded, the 'ROM/CRP' pattern was no longer associated with CRC risk, suggesting potential influence of preclinical disease on these associations. By application of PCA, the study identified 'HDL-C/Adiponectin fractions', 'ROM/CRP' and 'leptin/sOB-R' as biomarker patterns representing potentially important pathways for CRC development

Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer

Aleksandrova K., Boeing H., Nothlings U., Jenab M., Fedirko V., Kaaks R., Lukanova A., Trichopoulou A., Trichopoulos D., Boffetta P., Trepo E., Westhpal S., Duarte-Salles T., Stepien M., Overvad K., Tjonneland A., Halkjaer J., Boutron-Ruault M.C., Dossus L., Racine A., Lagiou P., Bamia C., Benetou V., Agnoli C., Palli D., Panico S., Tumino R., Vineis P., Bueno-de-Mesquita B., Peeters P.H., Gram I.T., Lund E., Weiderpass E., Quiros J.R., Agudo A., Sanchez M.J., Gavrila D., Barricarte A., Dorronsoro M., Ohlsson B., Lindkvist B., Johansson A., Sund M., Khaw K.T., Wareham N., Travis R.C., Riboli E., Pischon T.

Hepatology; 2014; 60(3): 858-871

Abstract as provided by PubMed

Obesity and associated metabolic disorders have been implicated in liver carcinogenesis; however, there are little data on the role of obesity-related biomarkers on liver cancer risk. We studied prospectively the association of inflammatory and metabolic biomarkers with risks of hepatocellular carcinoma (HCC), intrahepatic bile duct (IBD), and gallbladder and biliary tract cancers outside of the liver (GBTC) in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Over an average of 7.7 years, 296 participants developed HCC (n = 125), GBTC (n = 137), or IBD (n = 34). Using risk-set sampling, controls were selected in a 2:1 ratio and matched for recruitment center, age, sex, fasting status, and time of blood collection. Baseline serum concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), C-peptide, total high-molecular-weight (HMW) adiponectin, leptin, fetuin-a, and glutamatdehydrogenase (GLDH) were measured, and incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. After adjustment for lifestyle factors, diabetes, hepatitis infection, and adiposity measures, higher concentrations of CRP, IL-6, C-peptide, and non-HMW adiponectin were associated with higher risk of HCC (IRR per doubling of concentrations = 1.22; 95% CI = 1.02-1.46; P = 0.03; 1.90; 95% CI = 1.30-2.77; P = 0.001; 2.25; 95% CI = 1.43-3.54; P = 0.0005; and 2.09; 95% CI = 1.19-3.67; P = 0.01, respectively). CRP was associated also with risk of GBTC (IRR = 1.22; 95% CI = 1.05-1.42; P = 0.01). GLDH was associated with risks of HCC (IRR = 1.62; 95% CI = 1.25-2.11; P = 0.0003) and IBD (IRR = 10.5; 95% CI = 2.20-50.90; P = 0.003). The continuous net reclassification index was 0.63 for CRP, IL-6, C-peptide, and non-HMW adiponectin and 0.46 for GLDH, indicating good predictive ability of these biomarkers. CONCLUSION: Elevated levels of biomarkers of inflammation and hyperinsulinemia are associated with a higher risk of HCC, independent of obesity and established liver cancer risk factors. (Hepatology 2014;60:858-871)

Adiposity, mediating biomarkers and risk of colon cancer in the European prospective investigation into cancer and nutrition study

Aleksandrova K., Drogan D., Boeing H., Jenab M., Bas Bueno-de-Mesquita H., Jansen E., van Duijnhoven F.J., Rinaldi S., Fedirko V., Romieu I., Kaaks R., Riboli E., Gunter M.J., Romaguera D., Westhpal S., Overvad K., Tjonneland A., Halkjaer J., Boutron-Ruault M.C., Clavel-Chapelon F., Lukanova A., Trichopoulou A., Trichopoulos D., Vidalis P., Panico S., Agnoli C., Palli D., Tumino R., Vineis P., Buckland G., Sanchez-Cruz J.J., Dorronsoro M., Diaz M.J., Barricarte A., Ramon Quiros J., Peeters P.H., May A.M., Hallmans G., Palmqvist R., Crowe F.L., Khaw K.T., Wareham N., Pischon T.

Int J Cancer; 2014; 134(3): 612-621

Abstract as provided by PubMed

Adiposity is a risk factor for colon cancer, but underlying mechanisms are not well understood. We evaluated the extent to which 11 biomarkers with inflammatory and metabolic actions mediate the association of adiposity measures, waist circumference (WC) and body mass index (BMI), with colon cancer in men and women. We analyzed data from a prospective nested case-control study among 662 incident colon cancer cases matched within risk sets to 662 controls. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. The percent effect change and corresponding CIs were estimated after adjusting for biomarkers shown to be associated with colon cancer risk. After multivariable adjustment, WC was associated with colon cancer risk in men (top vs. bottom tertile RR 1.68, 95% CI 1.06-2.65; ptrend = 0.02) and in women (RR 1.67, 95% CI 1.09-2.56; ptrend = 0.03). BMI was associated with risk only in men. The association of WC with colon cancer was accounted mostly for by three biomarkers, high-density lipoprotein cholesterol, non-high-molecular-weight adiponectin and soluble leptin receptor, which in combination explained 46% (95% CI 37-57%) of the association in men and 50% (95% CI 40-65%) of the association in women. Similar results were observed for the associations with BMI in men. These data suggest that alterations in levels of these metabolic biomarkers may represent a primary mechanism of action in the relation of adiposity with colon cancer. Further studies are warranted to determine whether altering their concentrations may reduce colon cancer risk

Adherence to the Mediterranean diet and risk of bladder cancer in the EPIC cohort study

Buckland G., Ros M.M., Roswall N., Bueno-de-Mesquita H.B., Travier N., Tjonneland A., Kiemeney L.A., Sacerdote C., Tumino R., Ljungberg B., Gram I.T., Weiderpass E., Skeie G., Malm J., Ehrnstrom R., Chang-Claude J., Mattiello A., Agnoli C., Peeters P.H., Boutron-Ruault M.C., Fagherazzi G., Clavel-Chapelon F., Nilsson L.M., Amiano P., Trichopoulou A., Oikonomou E., Tsiotas K., Sanchez M.J., Overvad K., Quiros J.R., Chirlaque M.D., Barricarte A., Key T.J., Allen N.E., Khaw K.T., Wareham N., Riboli E., Kaaks R., Boeing H., Palli D., Romieu I., Romaguera D., Gonzalez C.A.

Int J Cancer; 2014; 134(10): 2504-2511

Abstract as provided by PubMed

There is growing evidence of the protective role of the Mediterranean diet (MD) on cancer. However, to date no epidemiological study has investigated the influence of the MD on bladder cancer. We evaluated the association between adherence to the MD and risk of urothelial cell bladder cancer (UCC), according to tumor aggressiveness, in the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 477,312 participants, recruited from ten European countries between 1991 and 2000. Information from validated dietary questionnaires was used to develop a relative Mediterranean diet score (rMED), including nine dietary components. Cox regression models were used to assess the effect of the rMED on UCC risk, while adjusting for dietary energy and tobacco smoking of any kind. Stratified analyses were performed by sex, BMI, smoking status, European region and age at diagnosis. During an average follow-up of 11 years, 1,425 participants (70.9% male) were diagnosed with a first primary UCC. There was a negative but non-significant association between a high versus low rMED score and risk of UCC overall (HR: 0.84 [95% CI 0.69, 1.03]) and risk of aggressive (HR: 0.88 [95% CI 0.61, 1.28]) and non-aggressive tumors (HR: 0.78 [95% CI 0.54, 1.14]). Although there was no effect modification in the stratified analyses, there was a significant 34% (p = 0.043) decreased risk of UCC in current smokers with a high rMED score. In EPIC, the MD was not significantly associated with risk of UCC, although we cannot exclude that a MD may reduce risk in current smokers

Leukocyte telomere length in relation to pancreatic cancer risk: a prospective study

Campa D., Mergarten B., De Vivo I, Boutron-Ruault M.C., Racine A., Severi G., Nieters A., Katzke V.A., Trichopoulou A., Yiannakouris N., Trichopoulos D., Boeing H., Quiros J.R., Duell E.J., Molina-Montes E., Huerta J.M., Ardanaz E., Dorronsoro M., Khaw K.T., Wareham N., Travis R.C., Palli D., Pala V., Tumino R., Naccarati A., Panico S., Vineis P., Riboli E., Siddiq A., Bueno-de-Mesquita H.B., Peeters P.H., Nilsson P.M., Sund M., Ye W., Lund E., Jareid M., Weiderpass E., Duarte-Salles T., Kong S.Y., Stepien M., Canzian F., Kaaks R.

Cancer Epidemiol Biomarkers Prev; 2014; 23(11): 2447-2454

Abstract as provided by PubMed

BACKGROUND: Several studies have examined leukocyte telomere length (LTL) as a possible predictor for cancer at various organ sites. The hypothesis originally motivating many of these studies was that shorter telomeres would be associated with an increase in cancer risk; the results of epidemiologic studies have been inconsistent, however, and suggested positive, negative, or null associations. Two studies have addressed the association of LTL in relation to pancreatic cancer risk and the results are contrasting. METHODS: We measured LTL in a prospective study of 331 pancreatic cancer cases and 331 controls in the context of the European Prospective Investigation into Cancer and Nutrition (EPIC). RESULTS: We observed that the mean LTL was higher in cases (0.59 +/- 0.20) than in controls (0.57 +/- 0.17), although this difference was not statistically significant (P = 0.07), and a basic logistic regression model showed no association of LTL with pancreas cancer risk. When adjusting for levels of HbA1c and C-peptide, however, there was a weakly positive association between longer LTL and pancreatic cancer risk [OR, 1.13; 95% confidence interval (CI), 1.01-1.27]. Additional analyses by cubic spline regression suggested a possible nonlinear relationship between LTL and pancreatic cancer risk (P = 0.022), with a statistically nonsignificant increase in risk at very low LTL, as well as a significant increase at high LTL. CONCLUSION: Taken together, the results from our study do not support LTL as a uniform and strong predictor of pancreatic cancer. IMPACT: The results of this article can provide insights into telomere dynamics and highlight the complex relationship between LTL and pancreatic cancer risk

Prospective seroepidemiologic study on the role of Human Papillomavirus and other infections in cervical carcinogenesis: evidence from the EPIC cohort

Castellsague X., Pawlita M., Roura E., Margall N., Waterboer T., Bosch F.X., de Sanjose S., Gonzalez C.A., Dillner J., Gram I.T., Tjonneland A., Munk C., Pala V., Palli D., Khaw K.T., Barnabas R.V., Overvad K., Clavel-Chapelon F., Boutron-Ruault M.C., Fagherazzi G., Kaaks R., Lukanova A., Steffen A., Trichopoulou A., Trichopoulos D., Klinaki E., Tumino R., Sacerdote C., Mattiello A., Bueno-de-Mesquita H.B., Peeters P.H., Lund E., Weiderpass E., Quiros J.R., Sanchez M.J., Navarro C., Barricarte A., Larranaga N., Ekstrom J., Hortlund M., Lindquist D., Wareham N., Travis R.C., Rinaldi S., Tommasino M., Franceschi S., Riboli E.

Int J Cancer; 2014; 135(2): 440-452

Abstract as provided by PubMed

To evaluate prospectively the association between serological markers of selected infections, including HPV, and risk of developing cervical cancer (CC) and precancer, we performed a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) study that included 184 cases of invasive CC (ICC), 425 cases of cervical intraepithelial neoplasia (CIN) grade 3 or carcinoma in situ (CIS), and 1,218 matched control women. At enrollment participants completed lifestyle questionnaires and provided sera. Subjects were followed-up for a median of 9 years. Immunoassays were used to detect serum antibodies to Human Herpes Virus 2 (HHV-2), Chlamydia trachomatis (CT), Chlamydia pneumoniae, L1 proteins of mucosal and cutaneous HPV types, E6/E7 proteins of HPV16/18, as well as to four polyomaviruses. Adjusted odds ratios (OR) [and 95% confidence intervals (CI)] for CIN3/CIS and ICC risk were respectively: 1.6 (1.2-2.0) and 1.8 (1.1-2.7) for L1 seropositivity to any mucosal HPV type, 1.0 (0.4-2.4) and 7.4 (2.8-19.7) for E6 seropositivity to HPV16/18, 1.3 (0.9-1.9) and 2.3 (1.3-4.1) for CT seropositivity, and 1.4 (1.0-2.0) and 1.5 (0.9-2.6) for HHV-2 seropositivity. The highest OR for ICC was observed for HPV16 E6 seropositivity [OR = 10.2 (3.3-31.1)]. Increasing number of sexually transmitted infections (STIs) was associated with increasing risk. Non-STIs were not associated with CC risk. In conclusion, this large prospective study confirms the important role of HPV and a possible contribution of CT and HHV-2 in cervical carcinogenesis. It further identifies HPV16 E6 seropositivity as the strongest marker to predict ICC well before disease development

Circulating biomarkers of tryptophan and the kynurenine pathway and lung cancer risk

Chuang S.C., Fanidi A., Ueland P.M., Relton C., Midttun O., Vollset S.E., Gunter M.J., Seckl M.J., Travis R.C., Wareham N., Trichopoulou A., Lagiou P., Trichopoulos D., Peeters P.H., Bueno-de-Mesquita H.B., Boeing H., Wientzek A., Kuehn T., Kaaks R., Tumino R., Agnoli C., Palli D., Naccarati A., Aicua E.A., Sanchez M.J., Quiros J.R., Chirlaque M.D., Agudo A., Johansson M., Grankvist K., Boutron-Ruault M.C., Clavel-Chapelon F., Fagherazzi G., Weiderpass E., Riboli E., Brennan P.J., Vineis P., Johansson M.

Cancer Epidemiol Biomarkers Prev; 2014; 23(3): 461-468

Abstract as provided by PubMed

BACKGROUND: Imbalances in tryptophan metabolism have been linked to cancer-related immune escape and implicated in several cancers, including lung cancer. METHODS: We conducted a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) that included 893 incident lung cancer cases and 1,748 matched controls. Circulating levels of tryptophan and six of its metabolites were measured and evaluated in relation to lung cancer risk. RESULTS: Tryptophan (Ptrend = 2 x 10(-5)) and the kynurenine/tryptophan ratio (KTR; Ptrend = 4 x 10(-5)) were associated with lung cancer risk overall after adjusting for established risk factors. The ORs comparing the fifth and first quintiles (OR5th vs. 1st) were 0.52 [95% confidence interval (CI), 0.37-0.74] for tryptophan and 1.74 (95% CI, 1.24-2.45) for KTR. After adjusting for plasma methionine (available from previous work, which was strongly correlated with tryptophan), the associations of tryptophan (adjusted Ptrend = 0.13) and KTR (Ptrend = 0.009) were substantially attenuated. KTR was positively associated with squamous cell carcinoma, the OR5th vs. 1st being 2.83 (95% CI, 1.62-4.94, Ptrend = 3 x 10(-5)) that was only marginally affected by adjusting for methionine. CONCLUSIONS: This study indicates that biomarkers of tryptophan metabolism are associated with subsequent lung cancer risk. Although this result would seem consistent with the immune system having a role in lung cancer development, the overall associations were dependent on methionine, and further studies are warranted to further elucidate the importance of these metabolites in lung cancer etiology. IMPACT: This is the first prospective study investigating the tryptophan pathway in relation to lung cancer risk

Polymorphisms of Helicobacter pylori signaling pathway genes and gastric cancer risk in the European Prospective Investigation into Cancer-Eurgast cohort

Companioni O., Bonet C., Munoz X., Weiderpass E., Panico S., Tumino R., Palli D., Agnoli C., Vineis P., Boutron-Ruault M.C., Racine A., Clavel-Chapelon F., Travis R.C., Khaw K.T., Riboli E., Murphy N., Vergnaud A.C., Trichopoulou A., Benetou V., Trichopoulos D., Lund E., Johansen D., Lindkvist B., Johansson M., Sund M., Ardanaz E., Sanchez-Cantalejo E., Huerta J.M., Dorronsoro M., Ramon Quiros J., Tjonneland A., Mortensen L.M., Overvad K., Chang-Claude J., Rizzato C., Boeing H., de Mesquita H.B., Siersema P., Peeters P.H., Numans M.E., Carneiro F., Licaj I., Freisling H., Sala N., Gonzalez C.A.

Int J Cancer; 2014; 134(1): 92-101

Abstract as provided by PubMed

Helicobacter pylori is a recognized causal factor of noncardia gastric cancer (GC). Lipopolysaccharide and peptidoglycan of this bacterium are recognized by CD14, TLR4 and NOD2 human proteins, while NFKB1 activates the transcription of pro-inflammatory cytokines to elicit an immune response. Single nucleotide polymorphisms (SNPs) in these genes have been associated with GC in different populations. We genotyped 30 SNPs of these genes, in 365 gastric adenocarcinomas and 1,284 matched controls from the European Prospective Investigation into Cancer cohort. The association with GC and its histological and anatomical subtypes was analyzed by logistic regression and corrected for multiple comparisons. Using a log-additive model, we found a significant association between SNPs in CD14, NOD2 and TLR4 with GC risk. However, after applying the multiple comparisons tests only the NOD2 region remained significant (p = 0.009). Analysis according to anatomical subtypes revealed NOD2 and NFKB1 SNPs associated with noncardia GC and CD14 SNPs associated with cardia GC, while analysis according to histological subtypes showed that CD14 was associated with intestinal but not diffuse GC. The multiple comparisons tests confirmed the association of NOD2 with noncardia GC (p = 0.0003) and CD14 with cardia GC (p = 0.01). Haplotype analysis was in agreement with single SNP results for NOD2 and CD14 genes. From these results, we conclude that genetic variation in NOD2 associates with noncardia GC while variation in CD14 is associated with cardia GC

Active and passive cigarette smoking and breast cancer risk: results from the EPIC cohort

Dossus L., Boutron-Ruault M.C., Kaaks R., Gram I.T., Vilier A., Fervers B., Manjer J., Tjonneland A., Olsen A., Overvad K., Chang-Claude J., Boeing H., Steffen A., Trichopoulou A., Lagiou P., Sarantopoulou M., Palli D., Berrino F., Tumino R., Vineis P., Mattiello A., Bueno-de-Mesquita H.B., van Duijnhoven F.J., Bakker M.F., Peeters P.H., Weiderpass E., Bjerkaas E., Braaten T., Menendez V., Agudo A., Sanchez M.J., Amiano P., Tormo M.J., Barricarte A., Butt S., Khaw K.T., Wareham N., Key T.J., Travis R.C., Rinaldi S., McCormack V., Romieu I., Cox D.G., Norat T., Riboli E., Clavel-Chapelon F.

Int J Cancer; 2014; 134(8): 1871-1888

Abstract as provided by PubMed

Recent cohort studies suggest that increased breast cancer risks were associated with longer smoking duration, higher pack-years and a dose-response relationship with increasing pack-years of smoking between menarche and first full-term pregnancy (FFTP). Studies with comprehensive quantitative life-time measures of passive smoking suggest an association between passive smoking dose and breast cancer risk. We conducted a study within the European Prospective Investigation into Cancer and Nutrition to examine the association between passive and active smoking and risk of invasive breast cancer and possible effect modification by known breast cancer risk factors. Among the 322,988 women eligible for the study, 9,822 developed breast cancer (183,608 women with passive smoking information including 6,264 cases). When compared to women who never smoked and were not being exposed to passive smoking at home or work at the time of study registration, current, former and currently exposed passive smokers were at increased risk of breast cancer (hazard ratios (HR) [95% confidence interval (CI)] 1.16 [1.05-1.28], 1.14 [1.04-1.25] and 1.10 [1.01-1.20], respectively). Analyses exploring associations in different periods of life showed the most important increase in risk with pack-years from menarche to FFTP (1.73 [1.29-2.32] for every increase of 20 pack-years) while pack-years smoked after menopause were associated with a significant decrease in breast cancer risk (HR = 0.53, 95% CI: 0.34-0.82 for every increase of 20 pack-years). Our results provide an important replication, in the largest cohort to date, that smoking (passively or actively) increases breast cancer risk and that smoking between menarche and FFTP is particularly deleterious

Dairy products and risk of hepatocellular carcinoma: The European Prospective Investigation into Cancer and Nutrition

Duarte-Salles T., Fedirko V., Stepien M., Trichopoulou A., Bamia C., Lagiou P., Lukanova A., Trepo E., Overvad K., Tjonneland A., Halkjaer J., Boutron-Ruault M.C., Racine A., Cadeau C., Kuhn T., Aleksandrova K., Trichopoulos D., Tsiotas K., Boffetta P., Palli D., Pala V., Tumino R., Sacerdote C., Panico S., Bueno-de-Mesquita H.B., Dik V.K., Peeters P.H., Weiderpass E., Torhild Gram I, Hjartaker A., Ramon Quiros J., Fonseca-Nunes A., Molina-Montes E., Dorronsoro M., Navarro Sanchez C., Barricarte A., Lindkvist B., Sonestedt E., Johansson I., Wennberg M., Khaw K.T., Wareham N., Travis R.C., Romieu I., Riboli E., Jenab M.

Int J Cancer; 2014; 135(7): 1662-1672

Abstract as provided by PubMed

Intake of dairy products has been associated with risk of some cancers, but findings are often inconsistent and information on hepatocellular carcinoma (HCC) risk is limited, particularly from prospective settings. The aim of our study was to investigate the association between consumption of total and specific dairy products (milk/cheese/yogurt) and their components (calcium/vitamin D/fats/protein), with first incident HCC (Ncases = 191) in the European Prospective Investigation into Cancer and Nutrition cohort, including a nested case-control subset (Ncases = 122) with the assessment of hepatitis B virus/hepatitis C virus infections status, liver damage and circulating insulin-like growth factor (IGF)-I levels. For cohort analyses, multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI). For nested case-control analyses, conditional logistic regression was used to calculate odds ratios and 95% CI. A total of 477,206 participants were followed-up for an average of 11 years (person-years follow-up = 5,415,385). In the cohort study, a significant positive HCC risk association was observed for total dairy products (highest vs. lowest tertile, HR = 1.66, 95% CI: 1.13-2.43; ptrend = 0.012), milk (HR = 1.51, 95% CI: 1.02-2.24; ptrend = 0.049), and cheese (HR = 1.56, 95% CI: 1.02-2.38; ptrend = 0.101), but not yogurt (HR = 0.94, 95% CI: 0.65-1.35). Dietary calcium, vitamin D, fat and protein from dairy sources were associated with increased HCC risk, whereas the same nutrients from nondairy sources showed inverse or null associations. In the nested case-control study, similar results were observed among hepatitis-free individuals. Results from this large prospective cohort study suggest that higher consumption of dairy products, particularly milk and cheese, may be associated with increased HCC risk. Validation of these findings in other populations is necessary. Potential biologic mechanisms require further exploration

Normalization to specific gravity prior to analysis improves information recovery from high resolution mass spectrometry metabolomic profiles of human urine

Edmands W.M., Ferrari P., Scalbert A.

Anal Chem; 2014; 86(21): 10925-10931

Abstract as provided by PubMed

Extraction of meaningful biological information from urinary metabolomic profiles obtained by liquid-chromatography coupled to mass spectrometry (MS) necessitates the control of unwanted sources of variability associated with large differences in urine sample concentrations. Different methods of normalization either before analysis (preacquisition normalization) through dilution of urine samples to the lowest specific gravity measured by refractometry, or after analysis (postacquisition normalization) to urine volume, specific gravity and median fold change are compared for their capacity to recover lead metabolites for a potential future use as dietary biomarkers. Twenty-four urine samples of 19 subjects from the European Prospective Investigation into Cancer and nutrition (EPIC) cohort were selected based on their high and low/nonconsumption of six polyphenol-rich foods as assessed with a 24 h dietary recall. MS features selected on the basis of minimum discriminant selection criteria were related to each dietary item by means of orthogonal partial least-squares discriminant analysis models. Normalization methods ranked in the following decreasing order when comparing the number of total discriminant MS features recovered to that obtained in the absence of normalization: preacquisition normalization to specific gravity (4.2-fold), postacquisition normalization to specific gravity (2.3-fold), postacquisition median fold change normalization (1.8-fold increase), postacquisition normalization to urinary volume (0.79-fold). A preventative preacquisition normalization based on urine specific gravity was found to be superior to all curative postacquisition normalization methods tested for discovery of MS features discriminant of dietary intake in these urinary metabolomic datasets

Weight change in middle adulthood and breast cancer risk in the EPIC-PANACEA study

Emaus M.J., Van Gils C.H., Bakker M.F., Bisschop C.N., Monninkhof E.M., Bueno-de-Mesquita H.B., Travier N., Berentzen T.L., Overvad K., Tjonneland A., Romieu I., Rinaldi S., Chajes V., Gunter M.J., Clavel-Chapelon F., Fagherazzi G., Mesrine S., Chang-Claude J., Kaaks R., Boeing H., Aleksandrova K., Trichopoulou A., Naska A., Orfanos P., Palli D., Agnoli C., Tumino R., Vineis P., Mattiello A., Braaten T., Borch K.B., Lund E., Menendez V., Sanchez M.J., Navarro C., Barricarte A., Amiano P., Sund M., Andersson A., Borgquist S., Olsson A., Khaw K.T., Wareham N., Travis R.C., Riboli E., Peeters P.H., May A.M.

Int J Cancer; 2014; 135(12): 2887-2899

Abstract as provided by PubMed

Long-term weight gain (i.e., weight gain since age 20) has been related to higher risk of postmenopausal breast cancer, but a lower risk of premenopausal breast cancer. The effect of weight change in middle adulthood is unclear. We investigated the association between weight change in middle adulthood (i.e., women aged 40-50 years) and the risk of breast cancer before and after the age of 50. We included female participants of the European Prospective Investigation into Cancer and Nutrition cohort, with information on anthropometric measures at recruitment and after a median follow-up of 4.3 years. Annual weight change was categorized using quintiles taking quintile 2 and 3 as the reference category (-0.44 to 0.36 kg/year). Multivariable Cox proportional hazards regression analysis was used to examine the association. 205,723 women were included and 4,663 incident breast cancer cases were diagnosed during a median follow-up of 7.5 years (from second weight assessment onward). High weight gain (Q5: 0.83-4.98 kg/year) was related to a slightly, but significantly higher breast cancer risk (HRQ5_versus_Q2/3 : 1.09, 95% CI: 1.01-1.18). The association was more pronounced for breast cancer diagnosed before or at age 50 (HRQ5_versus_Q2/3 : 1.37, 95% CI: 1.02-1.85). Weight loss was not associated with breast cancer risk. There was no evidence for heterogeneity by hormone receptor status. In conclusion, high weight gain in middle adulthood increases the risk of breast cancer. The association seems to be more pronounced for breast cancer diagnosed before or at age 50. Our results illustrate the importance of avoiding weight gain in middle adulthood

Genetic association of gastric cancer with miRNA clusters including the cancer-related genes MIR29, MIR25, MIR93 and MIR106: Results from the EPIC-EURGAST study

Espinosa-Parrilla Y., Munoz X., Bonet C., Garcia N., Vencesla A., Yiannakouris N., Naccarati A., Sieri S., Panico S., Huerta J.M., Barricarte A., Menendez V., Sanchez-Cantalejo E., Dorronsoro M., Brennan P., Duarte-Salles T., Bueno-de-Mesquita B.As, Weiderpass E., Lund E., Clavel-Chapelon F., Boutron-Ruault M.C., Racine A., Numans M.E., Tumino R., Canzian F., Campa D., Sund M., Johansson M., Ohlsson B., Lindkvist B., Overvad K., Tjonneland A., Palli D., Travis R.C., Khaw K.T., Wareham N., Boeing H., Nesi G., Riboli E., Gonzalez C.A., Sala N.

Int J Cancer; 2014; 135(9): 2065-2076

Abstract as provided by PubMed

MicroRNAs (miRNAs) are post-transcriptional gene regulators involved in a wide range of biological processes including tumorigenesis. Deregulation of miRNA pathways has been associated with cancer but the contribution of their genetic variability to this disorder is poorly known. We analyzed the genetic association of gastric cancer (GC) and its anatomical and histological subtypes, with 133 single-nucleotide polymorphisms (SNPs) tagging 15 isolated miRNAs and 24 miRNA clusters potentially involved in cancer, in 365 GC cases and 1,284 matched controls within the European Prospective Investigation into Cancer and Nutrition cohort. Various SNPs were associated with GC under the log-additive model. Furthermore, several of these miRNAs passed the gene-based permutation test when analyzed according to GC subtypes: three tagSNPs of the miR-29a/miR-29b-1 cluster were associated with diffuse subtype (minimum p-value = 1.7 x 10(-4) ; odds ratio, OR = 1.72; 95% confidence interval, CI = 1.30-2.28), two tagSNPs of the miR-25/miR-93/miR-106b cluster were associated with cardia GC (minimum p-value = 5.38 x 10(-3) ; OR = 0.56, 95% CI = 0.37-0.86) and one tagSNP of the miR-363/miR-92a-2/miR-19b-2/miR-20b/miR-18b/miR-106a cluster was associated with noncardia GC (minimum p-value = 5.40 x 10(-3) ; OR = 1.41, 95% CI = 1.12-1.78). Some functionally validated target genes of these miRNAs are implicated in cancer-related processes such as methylation (DNMT3A, DNMT3B), cell cycle (E2F1, CDKN1A, CDKN1C), apoptosis (BCL2L11, MCL1), angiogenesis (VEGFA) and progression (PIK3R1, MYCN). Furthermore, we identified genetic interactions between variants tagging these miRNAs and variants in their validated target genes. Deregulation of the expression of these miRNAs in GC also supports our findings, altogether suggesting for the fist time that genetic variation in MIR29, MIR25, MIR93 and MIR106b may have a critical role in genetic susceptibility to GC and could contribute to the molecular mechanisms of gastric carcinogenesis

Prediagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: A nested case-control study

Fedirko V., Duarte-Salles T., Bamia C., Trichopoulou A., Aleksandrova K., Trichopoulos D., Trepo E., Tjonneland A., Olsen A., Overvad K., Boutron-Ruault M.C., Clavel-Chapelon F., Kvaskoff M., Kuhn T., Lukanova A., Boeing H., Buijsse B., Klinaki E., Tsimakidi C., Naccarati A., Tagliabue G., Panico S., Tumino R., Palli D., Bueno-de-Mesquita H.B., Siersema P.D., Peters P.H., Lund E., Brustad M., Olsen K.S., Weiderpass E., Zamora-Ros R., Sanchez M.J., Ardanaz E., Amiano P., Navarro C., Quiros J.R., Werner M., Sund M., Lindkvist B., Malm J., Travis R.C., Khaw K.T., Stepien M., Scalbert A., Romieu I., Lagiou P., Riboli E., Jenab M.

Hepatology; 2014; 60(4): 1222-1230

Abstract as provided by PubMed

The association between vitamin D status and hepatocellular carcinoma (HCC) has not been well investigated, despite experimental evidence supporting an important role of vitamin D in liver pathophysiology. Our objective was to investigate the association between prediagnostic circulating 25-hydroxyvitamin D [25(OH)D] serum levels and the risk of HCC in a prospective, nested case-control study among 520,000 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Each case (n = 138) diagnosed between 1992 and 2010 was matched to one control by age, sex, study center, date and time of blood collection, and fasting status. Serum baseline levels of 25(OH)D were measured by liquid chromatography/tandem mass spectrometry. Multivariable incident rate ratios (IRRs) of HCC associated with continuous (per 10 nmol/L) or categorical levels (tertiles or a priori-defined categories) of prediagnostic 25(OH)D were calculated using conditional logistic regression. Higher 25(OH)D levels were associated with a 49% reduction in the risk of HCC (highest versus lowest tertile: multivariable IRR = 0.51, 95% confidence interval [CI], 0.26 to 0.99; Ptrend = 0.04; per 10 nmol/L increase: IRR = 0.80, 95% CI, 0.68-0.94). The finding did not vary substantially by time from enrolment to diagnosis, and did not change after adjustment for biomarkers of preexisting liver damage, nor chronic infection with hepatitis B or C viruses. The findings were not modified by body size or smoking status. CONCLUSION: In this prospective study on western European populations, serum levels of 25(OH)D were inversely associated with the risk of HCC. Given the rising incidence of this cancer in low-risk developed countries and the strong public health interest surrounding the potentially cancer-protective roles of vitamin D, additional studies in different populations are required. (Hepatology 2014;60:1222-1230)

Pre-diagnostic anthropometry and survival after colorectal cancer diagnosis in Western European populations

Fedirko V., Romieu I., Aleksandrova K., Pischon T., Trichopoulos D., Peeters P.H., Romaguera-Bosch D., Bueno-de-Mesquita H.B., Dahm C.C., Overvad K., Chirlaque M.D., Johansen C., Bidstrup P.E., Dalton S.O., Gunter M.J., Wark P.A., Norat T., Halkjaer J., Tjonneland A., Dik V.K., Siersema P.D., Boutron-Ruault M.C., Dossus L., Bastide N., Kuhn T., Kaaks R., Boeing H., Trichopoulou A., Klinaki E., Katsoulis M., Pala V., Panico S., Tumino R., Palli D., Vineis P., Weiderpass E., Skeie G., Gonzalez C.A., Sanchez M.J., Barricarte A., Amiano P., Quiros J.R., Manjer J., Jirstrom K., Ljuslinder I., Palmqvist R., Khaw K.T., Wareham N., Bradbury K.E., Stepien M., Duarte-Salles T., Riboli E., Jenab M.

Int J Cancer; 2014; 135(8): 1949-1960

Abstract as provided by PubMed

General and abdominal adiposity are associated with a high risk of developing colorectal cancer (CRC), but the role of these exposures on cancer survival has been less studied. The association between pre-diagnostic anthropometric characteristics and CRC-specific and all-cause death was examined among 3,924 men and women diagnosed with CRC between 1992 and 2009 in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Over a mean follow-up period of 49 months, 1,309 deaths occurred of which 1,043 (79.7%) were due to CRC. In multivariable analysis, pre-diagnostic BMI >/=30 kg/m(2) was associated with a high risk for CRC-specific (HR = 1.26, 95% CI = 1.04-1.52) and all-cause (HR = 1.32, 95% CI = 1.12-1.56) death relative to BMI <25 kg/m(2) . Every 5 kg/m(2) increase in BMI was associated with a high risk for CRC-specific (HR = 1.10, 95% CI = 1.02-1.19) and all-cause death (HR = 1.12, 95% CI = 1.05-1.20); and every 10 cm increase in waist circumference was associated with a high risk for CRC-specific (HR = 1.09, 95% CI = 1.02-1.16) and all-cause death (HR = 1.11, 95% CI = 1.05-1.18). Similar associations were observed for waist-to-hip and waist-to-height ratios. Height was not associated with CRC-specific or all-cause death. Associations tended to be stronger among men than in women. Possible interactions by age at diagnosis, cancer stage, tumour location, and hormone replacement therapy use among postmenopausal women were noted. Pre-diagnostic general and abdominal adiposity are associated with lower survival after CRC diagnosis

Lifetime alcohol use and overall and cause-specific mortality in the European Prospective Investigation into Cancer and nutrition (EPIC) study

Ferrari P., Licaj I., Muller D.C., Kragh Andersen P., Johansson M., Boeing H., Weiderpass E., Dossus L., Dartois L., Fagherazzi G., Bradbury K.E., Khaw K.T., Wareham N., Duell E.J., Barricarte A., Molina-Montes E., Sanchez C.N., Arriola L., Wallstrom P., Tjonneland A., Olsen A., Trichopoulou A., Benetou V., Trichopoulos D., Tumino R., Agnoli C., Sacerdote C., Palli D., Li K., Kaaks R., Peeters P., Beulens J.W., Nunes L., Gunter M., Norat T., Overvad K., Brennan P., Riboli E., Romieu I.

BMJ Open; 2014; 4(7): e005245

Abstract as provided by PubMed

OBJECTIVES: To investigate the role of factors that modulate the association between alcohol and mortality, and to provide estimates of absolute risk of death. DESIGN: The European Prospective Investigation into Cancer and nutrition (EPIC). SETTING: 23 centres in 10 countries. PARTICIPANTS: 380 395 men and women, free of cancer, diabetes, heart attack or stroke at enrolment, followed up for 12.6 years on average. MAIN OUTCOME MEASURES: 20 453 fatal events, of which 2053 alcohol-related cancers (ARC, including cancers of upper aerodigestive tract, liver, colorectal and female breast), 4187 cardiovascular diseases/coronary heart disease (CVD/CHD), 856 violent deaths and injuries. Lifetime alcohol use was assessed at recruitment. RESULTS: HRs comparing extreme drinkers (>/=30 g/day in women and >/=60 g/day in men) to moderate drinkers (0.1-4.9 g/day) were 1.27 (95% CI 1.13 to 1.43) in women and 1.53 (1.39 to 1.68) in men. Strong associations were observed for ARC mortality, in men particularly, and for violent deaths and injuries, in men only. No associations were observed for CVD/CHD mortality among drinkers, whereby HRs were higher in never compared to moderate drinkers. Overall mortality seemed to be more strongly related to beer than wine use, particularly in men. The 10-year risks of overall death for women aged 60 years, drinking more than 30 g/day was 5% and 7%, for never and current smokers, respectively. Corresponding figures in men consuming more than 60 g/day were 11% and 18%, in never and current smokers, respectively. In competing risks analyses, mortality due to CVD/CHD was more pronounced than ARC in men, while CVD/CHD and ARC mortality were of similar magnitude in women. CONCLUSIONS: In this large European cohort, alcohol use was positively associated with overall mortality, ARC and violent death and injuries, but marginally to CVD/CHD. Absolute risks of death observed in EPIC suggest that alcohol is an important determinant of total mortality

Adherence to predefined dietary patterns and incident type 2 diabetes in European populations: EPIC-InterAct Study

InterAct Consortium, Kroeger J., Slimani N., et al.

Diabetologia; 2014; 57(2): 321-333

Abstract as provided by PubMed

AIMS/HYPOTHESIS: Few studies have investigated the relationship between predefined dietary patterns and type 2 diabetes incidence; little is known about the generalisability of these associations. We aimed to assess the association between predefined dietary patterns and type 2 diabetes risk in European populations. METHODS: From among a case-cohort of 12,403 incident diabetes cases and 16,154 subcohort members nested within the prospective European Prospective Investigation into Cancer and Nutrition study, we used data on 9,682 cases and 12,595 subcohort participants from seven countries. Habitual dietary intake was assessed at baseline with country-specific dietary questionnaires. Two diet-quality scores (alternative Healthy Eating Index [aHEI], Dietary Approaches to Stop Hypertension [DASH] score) and three reduced rank regression (RRR)-derived dietary-pattern scores were constructed. Country-specific HRs were calculated and combined using a random-effects meta-analysis. RESULTS: After multivariable adjustment, including body size, the aHEI and DASH scores were not significantly associated with diabetes, although for the aHEI there was a tendency towards an inverse association in countries with higher mean age. We observed inverse associations of the three RRR-derived dietary-pattern scores with diabetes: HRs (95% CIs) for a 1-SD difference were 0.91 (0.86, 0.96), 0.92 (0.84, 1.01) and 0.87 (0.82, 0.92). Random-effects meta-analyses revealed heterogeneity between countries that was explainable by differences in the age of participants or the distribution of dietary intake. CONCLUSIONS/INTERPRETATION: Adherence to specific RRR-derived dietary patterns, commonly characterised by high intake of fruits or vegetables and low intake of processed meat, sugar-sweetened beverages and refined grains, may lower type 2 diabetes risk

Circulating biomarkers of one-carbon metabolism in relation to renal cell carcinoma incidence and survival

Johansson M., Fanidi A., Muller D.C., Bassett J.K., Midttun O., Vollset S.E., Travis R.C., Palli D., Mattiello A., Sieri S., Trichopoulou A., Lagiou P., Trichopoulos D., Ljungberg B., Hallmans G., Weiderpass E., Skeie G., Gonzalez C.A., Dorronsoro M., Peeters P.H., Bueno-de-Mesquita H.B., Ros M.M., Boutron Ruault M.C., Fagherazzi G., Clavel F., Sanchez M.J., Gurrea A.B., Navarro C., Quiros J.R., Overvad K., Tjonneland A., Aleksandrova K., Vineis P., Gunter M.J., Kaaks R., Giles G., Relton C., Riboli E., Boeing H., Ueland P.M., Severi G., Brennan P.

J Natl Cancer Inst; 2014; 106(12): pii: dju327

Abstract as provided by PubMed

BACKGROUND: The etiology of renal cell carcinoma (RCC) is only partially understood, but a metabolic component appears likely. We investigated biomarkers of one-carbon metabolism and RCC onset and survival. METHODS: The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 385747 participants with blood samples between 1992 and 2000, and this analysis included 556 RCC case-control pairs. A subsequent replication study included 144 case-control pairs nested within the Melbourne Collaborative Cohort Study (MCCS). Plasma concentrations of vitamin B2, vitamin B6, folate, vitamin B12, methionine and homocysteine were measured in prediagnostic samples and evaluated with respect to RCC risk using conditional and unconditional logistic regression models, and to all-cause mortality in RCC cases using Cox regression models. All statistical tests were two-sided. RESULTS: EPIC participants with higher plasma concentrations of vitamin B6 had lower risk of RCC, the odds ratio comparing the 4(th) and 1(st) quartiles (OR4vs1) being 0.40 95% confidence interval [CI] = 0.28 to 0.57, P trend < .001. We found similar results after adjusting for potential confounders (adjusted P trend < .001). In survival analysis, the hazard ratio for all-cause mortality in RCC cases when comparing the 4(th) and 1(st) quartiles (HR4vs1) of vitamin B6 was 0.57 (95% CI = 0.37 to 0.87, P trend < .001). Subsequent replication of these associations within the MCCS yielded very similar results for both RCC risk (OR4vs1 = 0.47, 95% CI = 0.23 to 0.99, P trend = .07) and all-cause mortality (HR4vs1 = 0.56, 95% CI = 0.27 to 1.17, P trend = .02). No association was evident for the other measured biomarkers. CONCLUSION: Study participants with higher circulating concentrations of vitamin B6 had lower risk of RCC and improved survival following diagnosis in two independent cohorts

Risk factors for cancers of unknown primary site: Results from the prospective EPIC cohort

Kaaks R., Sookthai D., Hemminki K., Kramer A., Boeing H., Wirfalt E., Weiderpass E., Overvad K., Tjonneland A., Olsen A., Peeters P.H., Bueno-de-Mesquita H.B., Panico S., Pala V., Vineis P., Quiros J.R., Ardanaz E., Sanchez M.J., Chirlaque M.D., Larranaga N., Brennan P., Trichopoulos D., Trichopoulou A., Lagiou P., Hallmans G., Khaw K.T., Key T.J., Riboli E., Canzian F.

Int J Cancer; 2014; 135(10): 2475-2481

Abstract as provided by PubMed

Cancer of unknown primary site (CUP) may be called an "orphan" disease, as it is diagnosed when metastases are detected while the primary tumor typically remains undetected, and because little research has been done on its primary causes. So far, few epidemiological studies, if any, have addressed possible risk factors for CUP. We analyzed data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (N = 476,940). During prospective follow-up, a total of 651 cases of incident cases of CUP were detected (ICD-O-2 code C809). Proportional hazards models were conducted to examine the associations of lifetime history of smoking habits, alcohol consumption, levels of education and anthropometric indices of adiposity with risk of being diagnosed with CUP. Risk of being diagnosed with CUP was strongly related to smoking, with a relative risk of 3.66 [95% C.I., 2.24-5.97] for current, heavy smokers (26+ cigarettes/day) compared to never smokers (adjusted for alcohol consumption, body mass index, waist circumference and level of education) and a relative risk of 5.12 [3.09-8.47] for cases with CUP who died within 12 months. For alcohol consumption and level of education, weaker associations were observed but attenuated and no longer statistically significant after adjusting for smoking and indices of obesity. Finally, risk of CUP was increased by approximately 30 per cent for subjects in the highest versus lowest quartiles of waist circumference. Our analyses provide further documentation, in addition to autopsy studies, that a substantial proportion of cancers of unknown primary site may have their origin in smoking-related tumors, in particular

Premenopausal serum sex hormone levels in relation to breast cancer risk, overall and by hormone receptor status-Results from the EPIC cohort

Kaaks R., Tikk K., Sookthai D., Schock H., Johnson T., Tjonneland A., Olsen A., Overvad K., Clavel-Chapelon F., Dossus L., Baglietto L., Rinaldi S., Chajes V., Romieu I., Boeing H., Schutze M., Trichopoulou A., Lagiou P., Trichopoulos D., Palli D., Sieri S., Tumino R., Ricceri F., Mattiello A., Buckland G., Ramon Quiros J., Sanchez M.J., Amiano P., Chirlaque M.D., Barricarte A., Bas Bueno-de-Mesquita H., Van Gils C.H., Peeters P.H., Andersson A., Sund M., Weiderpass E., Khaw K.T., Wareham N., Key T.J., Travis R.C., Merritt M.A., Gunter M.J., Riboli E., Lukanova A.

Int J Cancer; 2014; 134(8): 1947-1957

Abstract as provided by PubMed

Results from prospective studies on premenopausal serum hormone levels in relation to breast cancer risk have been inconclusive, especially with regard to tumor subtypes. Using a case-control study nested within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (801 breast cancer cases and 1,132 matched control subjects), we analyzed the relationships of prediagnostic serum estradiol, free estradiol, progesterone, testosterone, free testosterone and sex hormone-binding globulin (SHBG) levels with the risk of breast cancer by estrogen and progesterone receptor-positive and -negative breast tumors and by age at diagnoses. Higher prediagnostic serum levels of testosterone and free testosterone were associated with an increased overall risk of breast cancer [ORQ4-Q1 = 1.56 (95% CI 1.15-2.13), ptrend = 0.02 for testosterone and ORQ4-Q1 = 1.33 (95% CI 0.99-1.79), ptrend = 0.04 for free testosterone], but no significant risk association was observed for estradiol, free estradiol, progesterone and SHBG. Tests for heterogeneity between receptor-positive and -negative tumors were not significant. When analysis were stratified by age at tumor diagnosis, the odds ratios observed for estradiol were stronger and borderline significant for breast cancer diagnosed at age less than 50 [ORQ4-Q1 = 1.32 (95% CI 0.87-2.01), ptrend = 0.05] compared to breast cancer diagnosed at age 50 or above [ORQ4-Q1 = 0.94 (95% CI 0.60-1.47), ptrend = 0.34, phet = 0.04]. In conclusion, our data indicate that higher premenopausal circulating testosterone levels are associated with an increased risk of developing breast cancer, but do not show a significant association of estradiol or progesterone with breast cancer risk, overall, by menstrual cycle phase or by tumor receptor status, although a possible risk increase with higher estradiol levels for tumors diagnosed before age 50 was seen

Plasma alkylresorcinol concentrations, biomarkers of whole-grain wheat and rye intake, in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Kyro C., Olsen A., Bueno-de-Mesquita H.B., Skeie G., Loft S., Aman P., Leenders M., Dik V.K., Siersema P.D., Pischon T., Christensen J., Overvad K., Boutron-Ruault M.C., Fagherazzi G., Cottet V., Kuhn T., Chang-Claude J., Boeing H., Trichopoulou A., Naska A., Oikonomidou D., Masala G., Pala V., Tumino R., Vineis P., Mattiello A., Peeters P.H., Bakken T., Weiderpass E., Asli L.A., Sanchez S., Jakszyn P., Sanchez M.J., Amiano P., Huerta J.M., Barricarte A., Ljuslinder I., Palmqvist R., Khaw K.T., Wareham N., Key T.J., Travis R.C., Slimani N., Freisling H., Ferrari P., Gunter M.J., Murphy N., Riboli E., Tjonneland A., Landberg R.

Br J Nutr; 2014; 111(10): 1881-1890

Abstract as provided by PubMed

Whole-grain intake has been reported to be associated with a lower risk of several lifestyle-related diseases such as type 2 diabetes, CVD and some types of cancers. As measurement errors in self-reported whole-grain intake assessments can be substantial, dietary biomarkers are relevant to be used as complementary tools for dietary intake assessment. Alkylresorcinols (AR) are phenolic lipids found almost exclusively in whole-grain wheat and rye products among the commonly consumed foods and are considered as valid biomarkers of the intake of these products. In the present study, we analysed the plasma concentrations of five AR homologues in 2845 participants from ten European countries from a nested case-control study in the European Prospective Investigation into Cancer and Nutrition. High concentrations of plasma total AR were found in participants from Scandinavia and Central Europe and lower concentrations in those from the Mediterranean countries. The geometric mean plasma total AR concentrations were between 35 and 41 nmol/l in samples drawn from fasting participants in the Central European and Scandinavian countries and below 23 nmol/l in those of participants from the Mediterranean countries. The whole-grain source (wheat or rye) could be determined using the ratio of two of the homologues. The main source was wheat in Greece, Italy, the Netherlands and the UK, whereas rye was also consumed in considerable amounts in Germany, Denmark and Sweden. The present study demonstrates a considerable variation in the plasma concentrations of total AR and concentrations of AR homologues across ten European countries, reflecting both quantitative and qualitative differences in the intake of whole-grain wheat and rye

Plasma alkylresorcinols, biomarkers of whole-grain wheat and rye intake, and incidence of colorectal cancer

Kyro C., Olsen A., Landberg R., Skeie G., Loft S., Aman P., Leenders M., Dik V.K., Siersema P.D., Pischon T., Christensen J., Overvad K., Boutron-Ruault M.C., Fagherazzi G., Cottet V., Kuhn T., Chang-Claude J., Boeing H., Trichopoulou A., Bamia C., Trichopoulos D., Palli D., Krogh V., Tumino R., Vineis P., Panico S., Peeters P.H., Weiderpass E., Bakken T., Asli L.A., Arguelles M., Jakszyn P., Sanchez M.J., Amiano P., Huerta J.M., Barricarte A., Ljuslinder I., Palmqvist R., Khaw K.T., Wareham N., Key T.J., Travis R.C., Ferrari P., Freisling H., Jenab M., Gunter M.J., Murphy N., Riboli E., Tjonneland A., Bueno-de-Mesquita H.B.

J Natl Cancer Inst; 2014; 106(1): djt352

Abstract as provided by PubMed

BACKGROUND: Few studies have investigated the association between whole-grain intake and colorectal cancer. Because whole-grain intake estimation might be prone to measurement errors, more objective measures (eg, biomarkers) could assist in investigating such associations. METHODS: The association between alkylresorcinols, biomarkers of whole-grain rye and wheat intake, and colorectal cancer incidence were investigated using prediagnostic plasma samples from colorectal cancer case patients and matched control subjects nested within the European Prospective Investigation into Cancer and Nutrition. We included 1372 incident colorectal cancer case patients and 1372 individual matched control subjects and calculated the incidence rate ratios (IRRs) for overall and anatomical subsites of colorectal cancer using conditional logistic regression adjusted for potential confounders. Regional differences (Scandinavia, the Mediterranean, Central Europe) were also explored. RESULTS: High plasma total alkylresorcinol concentration was associated with lower incidence of distal colon cancer; the adjusted incidence rate ratio of distal colon cancer for the highest vs lowest quartile of plasma total alkylresorcinols was 0.48 (95% confidence interval [CI] = 0.28 to 0.83). An inverse association between plasma total alkylresorcinol concentrations and colon cancer was found for Scandinavian participants (IRR per doubling = 0.83; 95% CI = 0.70 to 0.98). However, plasma total alkylresorcinol concentrations were not associated with overall colorectal cancer, proximal colon cancer, or rectal cancer. Plasma alkylresorcinols concentrations were associated with colon and distal colon cancer only in Central Europe and Scandinavia (ie, areas where alkylresorcinol levels were higher). CONCLUSIONS: High concentrations of plasma alkylresorcinols were associated with a lower incidence of distal colon cancer but not with overall colorectal cancer, proximal colon cancer, and rectal cancer

Fruit and vegetable intake and cause-specific mortality in the EPIC study

Leenders M., Boshuizen H.C., Ferrari P., Siersema P.D., Overvad K., Tjonneland A., Olsen A., Boutron-Ruault M.C., Dossus L., Dartois L., Kaaks R., Li K., Boeing H., Bergmann M.M., Trichopoulou A., Lagiou P., Trichopoulos D., Palli D., Krogh V., Panico S., Tumino R., Vineis P., Peeters P.H., Weiderpass E., Engeset D., Braaten T., Redondo M.L., Agudo A., Sanchez M.J., Amiano P., Huerta J.M., Ardanaz E., Drake I., Sonestedt E., Johansson I., Winkvist A., Khaw K.T., Wareham N.J., Key T.J., Bradbury K.E., Johansson M., Licaj I., Gunter M.J., Murphy N., Riboli E., Bueno-de-Mesquita H.B.

Eur J Epidemiol; 2014; 29(9): 639-652

Abstract as provided by PubMed

Consumption of fruits and vegetables is associated with a lower overall mortality. The aim of this study was to identify causes of death through which this association is established. More than 450,000 participants from the European Prospective Investigation into Cancer and Nutrition study were included, of which 25,682 were reported deceased after 13 years of follow-up. Information on lifestyle, diet and vital status was collected through questionnaires and population registries. Hazard ratios (HR) with 95 % confidence intervals (95 % CI) for death from specific causes were calculated from Cox regression models, adjusted for potential confounders. Participants reporting consumption of more than 569 g/day of fruits and vegetables had lower risks of death from diseases of the circulatory (HR for upper fourth 0.85, 95 % CI 0.77-0.93), respiratory (HR for upper fourth 0.73, 95 % CI 0.59-0.91) and digestive system (HR for upper fourth 0.60, 95 % CI 0.46-0.79) when compared with participants consuming less than 249 g/day. In contrast, a positive association with death from diseases of the nervous system was observed. Inverse associations were generally observed for vegetable, but not for fruit consumption. Associations were more pronounced for raw vegetable consumption, when compared with cooked vegetable consumption. Raw vegetable consumption was additionally inversely associated with death from neoplasms and mental and behavioral disorders. The lower risk of death associated with a higher consumption of fruits and vegetables may be derived from inverse associations with diseases of the circulatory, respiratory and digestive system, and may depend on the preparation of vegetables and lifestyle factors

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