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2016

Healthy Lifestyle and Risk of Cancer in the European Prospective Investigation Into Cancer and Nutrition Cohort Study

McKenzie F., Biessy C., Ferrari P., Freisling H., Rinaldi S., Chajes V., Dahm C. C., Overvad K., Dossus L., Lagiou P., Trichopoulos D., Trichopoulou A., Bueno-de-Mesquita H. B., May A., Peeters P. H., Weiderpass E., Sanchez M. J., Navarro C., Ardanaz E., Ericson U., Wirfalt E., Travis R. C., Romieu I.

Medicine (Baltimore); 2016; 95(16): e2850

PMID:27100409

Abstract as provided by PubMed

It has been estimated that at least a third of the most common cancers are related to lifestyle and as such are preventable. Key modifiable lifestyle factors have been individually associated with cancer risk; however, less is known about the combined effects of these factors. This study generated a healthy lifestyle index score (HLIS) to investigate the joint effect of modifiable factors on the risk of overall cancers, alcohol-related cancers, tobacco-related cancers, obesity-related cancers, and reproductive-related cancers. The study included 391,608 men and women from the multinational European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The HLIS was constructed from 5 factors assessed at baseline (diet, physical activity, smoking, alcohol consumption, and anthropometry) by assigning scores of 0 to 4 to categories of each factor, for which higher values indicate healthier behaviors. Hazard ratios (HR) were estimated by Cox proportional regression and population attributable fractions (PAFs) estimated from the adjusted models. There was a 5% lower risk (adjusted HR 0.952, 95% confidence interval (CI): 0.946, 0.958) of all cancers per point score of the index for men and 4% (adjusted HR 0.961, 95% CI: 0.956, 0.966) for women. The fourth versus the second category of the HLIS was associated with a 28% and 24% lower risk for men and women respectively across all cancers, 41% and 33% for alcohol-related, 49% and 46% for tobacco-related, 41% and 26% for obesity-related, and 21% for female reproductive cancers. Findings suggest simple behavior modifications could have a sizeable impact on cancer prevention, especially for men.

Nutrient-wide association study of 57 foods/nutrients and epithelial ovarian cancer in the European Prospective Investigation into Cancer and Nutrition study and the Netherlands Cohort Study

Merritt M. A., Tzoulaki I., van den Brandt P. A., Schouten L. J., Tsilidis K. K., Weiderpass E., Patel C. J., Tjonneland A., Hansen L., Overvad K., His M., Dartois L., Boutron-Ruault M. C., Fortner R. T., Kaaks R., Aleksandrova K., Boeing H., Trichopoulou A., Lagiou P., Bamia C., Palli D., Krogh V., Tumino R., Ricceri F., Mattiello A., Bueno-de-Mesquita H. B., Onland-Moret N. C., Peeters P. H., Skeie G., Jareid M., Quiros J. R., Obon-Santacana M., Sanchez M. J., Chamosa S., Huerta J. M., Barricarte A., Dias J. A., Sonestedt E., Idahl A., Lundin E., Wareham N. J., Khaw K. T., Travis R. C., Ferrari P., Riboli E., Gunter M. J.

Am J Clin Nutr; 2016; 103(1): 161-7

PMID:26607939

Abstract as provided by PubMed

BACKGROUND: Studies of the role of dietary factors in epithelial ovarian cancer (EOC) development have been limited, and no specific dietary factors have been consistently associated with EOC risk. OBJECTIVE: We used a nutrient-wide association study approach to systematically test the association between dietary factors and invasive EOC risk while accounting for multiple hypothesis testing by using the false discovery rate and evaluated the findings in an independent cohort. DESIGN: We assessed dietary intake amounts of 28 foods/food groups and 29 nutrients estimated by using dietary questionnaires in the EPIC (European Prospective Investigation into Cancer and Nutrition) study (n = 1095 cases). We selected 4 foods/nutrients that were statistically significantly associated with EOC risk when comparing the extreme quartiles of intake in the EPIC study (false discovery rate = 0.43) and evaluated these factors in the NLCS (Netherlands Cohort Study; n = 383 cases). Cox regression models were used to estimate HRs and 95% CIs. RESULTS: None of the 4 dietary factors that were associated with EOC risk in the EPIC study (cholesterol, polyunsaturated and saturated fat, and bananas) were statistically significantly associated with EOC risk in the NLCS; however, in meta-analysis of the EPIC study and the NLCS, we observed a higher risk of EOC with a high than with a low intake of saturated fat (quartile 4 compared with quartile 1; overall HR: 1.21; 95% CI: 1.04, 1.41). CONCLUSION: In the meta-analysis of both studies, there was a higher risk of EOC with a high than with a low intake of saturated fat.

Flavonoid and lignan intake and pancreatic cancer risk in the European prospective investigation into cancer and nutrition cohort

Molina-Montes E., Sanchez M. J., Zamora-Ros R., Bueno-de-Mesquita H. B., Wark P. A., Obon-Santacana M., Kuhn T., Katzke V., Travis R. C., Ye W., Sund M., Naccarati A., Mattiello A., Krogh V., Martorana C., Masala G., Amiano P., Huerta J. M., Barricarte A., Quiros J. R., Weiderpass E., Angell Asli L., Skeie G., Ericson U., Sonestedt E., Peeters P. H., Romieu I., Scalbert A., Overvad K., Clemens M., Boeing H., Trichopoulou A., Peppa E., Vidalis P., Khaw K. T., Wareham N., Olsen A., Tjonneland A., Boutroun-Rualt M. C., Clavel-Chapelon F., Cross A. J., Lu Y., Riboli E., Duell E. J.

Int J Cancer; 2016; 139(7): 1480-92

PMID:27184434

Abstract as provided by PubMed

Despite the potential cancer preventive effects of flavonoids and lignans, their ability to reduce pancreatic cancer risk has not been demonstrated in epidemiological studies. Our aim was to examine the association between dietary intakes of flavonoids and lignans and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 865 exocrine pancreatic cancer cases occurred after 11.3 years of follow-up of 477,309 cohort members. Dietary flavonoid and lignan intake was estimated through validated dietary questionnaires and the US Department of Agriculture (USDA) and Phenol Explorer databases. Hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using age, sex and center-stratified Cox proportional hazards models, adjusted for energy intake, body mass index (BMI), smoking, alcohol and diabetes status. Our results showed that neither overall dietary intake of flavonoids nor of lignans were associated with pancreatic cancer risk (multivariable-adjusted HR for a doubling of intake = 1.03, 95% CI: 0.95-1.11 and 1.02; 95% CI: 0.89-1.17, respectively). Statistically significant associations were also not observed by flavonoid subclasses. An inverse association between intake of flavanones and pancreatic cancer risk was apparent, without reaching statistical significance, in microscopically confirmed cases (HR for a doubling of intake = 0.96, 95% CI: 0.91-1.00). In conclusion, we did not observe an association between intake of flavonoids, flavonoid subclasses or lignans and pancreatic cancer risk in the EPIC cohort.

Main nutrient patterns and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition study

Moskal A., Freisling H., Byrnes G., Assi N., Fahey M. T., Jenab M., Ferrari P., Tjonneland A., Petersen K. E., Dahm C. C., Hansen C. P., Affret A., Boutron-Ruault M. C., Cadeau C., Kuhn T., Katzke V., Iqbal K., Boeing H., Trichopoulou A., Bamia C., Naska A., Masala G., de Magistris M. S., Sieri S., Tumino R., Sacerdote C., Peeters P. H., Bueno-de-Mesquita B. H., Engeset D., Licaj I., Skeie G., Ardanaz E., Buckland G., Castano J. M., Quiros J. R., Amiano P., Molina-Portillo E., Winkvist A., Myte R., Ericson U., Sonestedt E., Perez-Cornago A., Wareham N., Khaw K. T., Huybrechts I., Tsilidis K. K., Ward H., Gunter M. J., Slimani N.

Br J Cancer; 2016; 115(11): 1430-1440

PMID:27764841

Abstract as provided by PubMed

BACKGROUND: Much of the current literature on diet-colorectal cancer (CRC) associations focused on studies of single foods/nutrients, whereas less is known about nutrient patterns. We investigated the association between major nutrient patterns and CRC risk in participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) study. METHODS: Among 477 312 participants, intakes of 23 nutrients were estimated from validated dietary questionnaires. Using results from a previous principal component (PC) analysis, four major nutrient patterns were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed for the association of each of the four patterns and CRC incidence using multivariate Cox proportional hazards models with adjustment for established CRC risk factors. RESULTS: During an average of 11 years of follow-up, 4517 incident cases of CRC were documented. A nutrient pattern characterised by high intakes of vitamins and minerals was inversely associated with CRC (HR per 1 s.d.=0.94, 95% CI: 0.92-0.98) as was a pattern characterised by total protein, riboflavin, phosphorus and calcium (HR (1 s.d.)=0.96, 95% CI: 0.93-0.99). The remaining two patterns were not significantly associated with CRC risk. CONCLUSIONS: Analysing nutrient patterns may improve our understanding of how groups of nutrients relate to CRC.

A Nested Case-Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Murphy N., Cross A. J., Abubakar M., Jenab M., Aleksandrova K., Boutron-Ruault M. C., Dossus L., Racine A., Kuhn T., Katzke V. A., Tjonneland A., Petersen K. E., Overvad K., Quiros J. R., Jakszyn P., Molina-Montes E., Dorronsoro M., Huerta J. M., Barricarte A., Khaw K. T., Wareham N., Travis R. C., Trichopoulou A., Lagiou P., Trichopoulos D., Masala G., Krogh V., Tumino R., Vineis P., Panico S., Bueno-de-Mesquita H. B., Siersema P. D., Peeters P. H., Ohlsson B., Ericson U., Palmqvist R., Nystrom H., Weiderpass E., Skeie G., Freisling H., Kong S. Y., Tsilidis K., Muller D. C., Riboli E., Gunter M. J.

PLoS Med; 2016; 13(4): e1001988

PMID:27046222

Abstract as provided by PubMed

BACKGROUND: Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown. METHODS AND FINDINGS: The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI >/= 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI >/= 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [>/=80 cm for women and >/=94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic-based on their C-peptide level-was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed. CONCLUSIONS: These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.

Sweet-beverage consumption and risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Navarrete-Munoz E. M., Wark P. A., Romaguera D., Bhoo-Pathy N., Michaud D., Molina-Montes E., Tjonneland A., Olsen A., Overvad K., Boutron-Ruault M. C., Clavel-Chapelon F., Fagherazzi G., Katzke V. A., Kuhn T., Steffen A., Trichopoulou A., Klinaki E., Papatesta E. M., Masala G., Krogh V., Tumino R., Naccarati A., Mattiello A., Peeters P. H., Rylander C., Parr C. L., Skeie G., Weiderpass E., Quiros J. R., Duell E. J., Dorronsoro M., Huerta J. M., Ardanaz E., Wareham N., Khaw K. T., Travis R. C., Key T., Stepien M., Freisling H., Riboli E., Bueno-de-Mesquita H. B.

Am J Clin Nutr; 2016; 104(3): 760-8

PMID:27510540

Abstract as provided by PubMed

BACKGROUND: The consumption of sweet beverages has been associated with greater risk of type 2 diabetes and obesity, which may be involved in the development of pancreatic cancer. Therefore, it has been hypothesized that sweet beverages may increase pancreatic cancer risk as well. OBJECTIVE: We examined the association between sweet-beverage consumption (including total, sugar-sweetened, and artificially sweetened soft drink and juice and nectar consumption) and pancreatic cancer risk. DESIGN: The study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort. A total of 477,199 participants (70.2% women) with a mean age of 51 y at baseline were included, and 865 exocrine pancreatic cancers were diagnosed after a median follow-up of 11.60 y (IQR: 10.10-12.60 y). Sweet-beverage consumption was assessed with the use of validated dietary questionnaires at baseline. HRs and 95% CIs were obtained with the use of multivariable Cox regression models that were stratified by age, sex, and center and adjusted for educational level, physical activity, smoking status, and alcohol consumption. Associations with total soft-drink consumption were adjusted for juice and nectar consumption and vice versa. RESULTS: Total soft-drink consumption (HR per 100 g/d: 1.03; 95% CI: 0.99, 1.07), sugar-sweetened soft-drink consumption (HR per 100 g/d: 1.02; 95% CI: 0.97, 1.08), and artificially sweetened soft-drink consumption (HR per 100 g/d: 1.04; 95% CI: 0.98, 1.10) were not associated with pancreatic cancer risk. Juice and nectar consumption was inversely associated with pancreatic cancer risk (HR per 100 g/d: 0.91; 95% CI: 0.84, 0.99); this association remained statistically significant after adjustment for body size, type 2 diabetes, and energy intake. CONCLUSIONS: Soft-drink consumption does not seem to be associated with pancreatic cancer risk. Juice and nectar consumption might be associated with a modest decreased pancreatic cancer risk. Additional studies with specific information on juice and nectar subtypes are warranted to clarify these results.

Compilation of a standardised international folate database for EPIC

Nicolas G., Witthoft C. M., Vignat J., Knaze V., Huybrechts I., Roe M., Finglas P., Slimani N.

Food Chem; 2016; 134-40

PMID:26433299

Abstract as provided by PubMed

This paper describes the methodology applied for compiling an "international end-user" folate database. This work benefits from the unique dataset offered by the European Prospective Investigation into Cancer and Nutrition (EPIC) (N=520,000 subjects in 23 centres). Compilation was done in four steps: (1) identify folate-free foods then find folate values for (2) folate-rich foods common across EPIC countries, (3) the remaining "common" foods, and (4) "country-specific" foods. Compiled folate values were concurrently standardised in terms of unit, mode of expression and chemical analysis, using information in national food composition tables (FCT). 43-70% total folate values were documented as measured by microbiological assay. Foods reported in EPIC were either matched directly to FCT foods, treated as recipes or weighted averages. This work has produced the first standardised folate dataset in Europe, which was used to calculate folate intakes in EPIC; a prerequisite to study the relation between folate intake and diseases.

Acrylamide and glycidamide hemoglobin adduct levels and endometrial cancer risk: A nested case-control study in nonsmoking postmenopausal women from the EPIC cohort

Obon-Santacana M., Freisling H., Peeters P. H., Lujan-Barroso L., Ferrari P., Boutron-Ruault M. C., Mesrine S., Baglietto L., Turzanski-Fortner R., Katzke V. A., Boeing H., Quiros J. R., Molina-Portillo E., Larranaga N., Chirlaque M. D., Barricarte A., Khaw K. T., Wareham N., Travis R. C., Merritt M. A., Gunter M. J., Trichopoulou A., Lagiou P., Naska A., Palli D., Sieri S., Tumino R., Fiano V., Galassom R., Bueno-de-Mesquita H. B., Onland-Moret N. C., Idahl A., Lundin E., Weiderpass E., Vesper H., Riboli E., Duell E. J.

Int J Cancer; 2016; 138(5): 1129-38

PMID:26376083

Abstract as provided by PubMed

Acrylamide, classified in 1994 by IARC as "probably carcinogenic to humans," was discovered in 2002 in some heat-treated, carbohydrate-rich foods. Four prospective studies have evaluated the association between dietary acrylamide intake and endometrial cancer (EC) risk with inconsistent results. The purpose of this nested case-control study, based on the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, was to evaluate, for the first time, the association between hemoglobin adducts of acrylamide (HbAA) and glycidamide (HbGA) and the risk of developing EC in non-smoking postmenopausal women. Hemoglobin adducts were measured in red blood cells by HPLC/MS/MS. Four exposure variables were evaluated: HbAA, HbGA, their sum (HbAA+HbGA), and their ratio (HbGA/HbAA). The association between hemoglobin adducts and EC was evaluated using unconditional multivariable logistic regression models, and included 383 EC cases (171 were type-I EC), and 385 controls. Exposure variables were analyzed in quintiles based on control distributions. None of the biomarker variables had an effect on overall EC (HRHbAA;Q5vsQ1 : 0.84, 95%CI: 0.49-1.48; HRHbGA;Q5vsQ1 : 0.94, 95%CI: 0.54-1.63) or type-I EC risk. Additionally, none of the subgroups investigated (BMI < 25 vs. >/=25 kg m(-2) , alcohol drinkers vs. never drinkers, oral contraceptive users vs. non-users) demonstrated effect measure modification. Hemoglobin adducts of acrylamide or glycidamide were not associated with EC or type-I EC risk in 768 nonsmoking postmenopausal women from the EPIC cohort.

Acrylamide and Glycidamide Hemoglobin Adducts and Epithelial Ovarian Cancer: A Nested Case-Control Study in Nonsmoking Postmenopausal Women from the EPIC Cohort

Obon-Santacana M., Lujan-Barroso L., Travis R. C., Freisling H., Ferrari P., Severi G., Baglietto L., Boutron-Ruault M. C., Fortner R. T., Ose J., Boeing H., Menendez V., Sanchez-Cantalejo E., Chamosa S., Castano J. M., Ardanaz E., Khaw K. T., Wareham N., Merritt M. A., Gunter M. J., Trichopoulou A., Papatesta E. M., Klinaki E., Saieva C., Tagliabue G., Tumino R., Sacerdote C., Mattiello A., Bueno-de-Mesquita H. B., Peeters P. H., Onland-Moret N. C., Idahl A., Lundin E., Weiderpass E., Vesper H. W., Riboli E., Duell E. J.

Cancer Epidemiol Biomarkers Prev; 2016; 25(1): 127-34

PMID:26598536

Abstract as provided by PubMed

BACKGROUND: Acrylamide was classified as "probably carcinogenic to humans (group 2A)" by the International Agency for Research on Cancer. Epithelial ovarian cancer (EOC) is the fourth cause of cancer mortality in women. Five epidemiological studies have evaluated the association between EOC risk and dietary acrylamide intake assessed using food frequency questionnaires, and one nested case-control study evaluated hemoglobin adducts of acrylamide (HbAA) and its metabolite glycidamide (HbGA) and EOC risk; the results of these studies were inconsistent. METHODS: A nested case-control study in nonsmoking postmenopausal women (334 cases, 417 controls) was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Unconditional logistic regression models were used to estimate ORs and 95% confidence intervals (CI) for the association between HbAA, HbGA, HbAA+HbGA, and HbGA/HbAA and EOC and invasive serous EOC risk. RESULTS: No overall associations were observed between biomarkers of acrylamide exposure analyzed in quintiles and EOC risk; however, positive associations were observed between some middle quintiles of HbGA and HbAA+HbGA. Elevated but nonstatistically significant ORs for serous EOC were observed for HbGA and HbAA+HbGA (ORQ5vsQ1, 1.91; 95% CI, 0.96-3.81 and ORQ5vsQ1, 1.90; 95% CI, 0.94-3.83, respectively); however, no linear dose-response trends were observed. CONCLUSION: This EPIC nested case-control study failed to observe a clear association between biomarkers of acrylamide exposure and the risk of EOC or invasive serous EOC. IMPACT: It is unlikely that dietary acrylamide exposure increases ovarian cancer risk; however, additional studies with larger sample size should be performed to exclude any possible association with EOC risk. Cancer Epidemiol Biomarkers Prev; 25(1); 127-34. (c)2015 AACR.

Evaluating Ultra-long-Chain Fatty Acids as Biomarkers of Colorectal Cancer Risk

Perttula Kelsi, Edmands William M. B., Grigoryan Hasmik, Cai Xiaoming, Iavarone Anthony T., Gunter Marc J., Naccarati Alessio, Polidoro Silvia, Hubbard Alan, Vineis Paolo, Rappaport Stephen M.

Cancer Epidemiol Biomarkers Prev; 2016; 25(8): 1216-23

PMID:27257090

Abstract as provided by PubMed

Background: Cross-sectional studies reported a novel set of hydroxylated ultra-long-chain fatty acids (ULCFA) that were present at significantly lower levels in colorectal cancer cases than controls. Follow-up studies suggested that these molecules were potential biomarkers of protective exposure for colorectal cancer. To test the hypothesis that ULCFAs reflect causal pathways, we measured their levels in prediagnostic serum from incident colorectal cancer cases and controls. Methods: Serum from 95 colorectal cancer patients and 95 matched controls was obtained from the Italian arm of the European Prospective Investigation into Cancer and Nutrition cohort and analyzed by liquid chromatography-high-resolution mass spectrometry. Levels of 8 ULCFAs were compared between cases and controls with paired t tests and a linear model that used time to diagnosis (TTD) to determine whether case-control differences were influenced by disease progression. Results: Although paired t tests detected significantly lower levels of four ULCFAs in colorectal cancer cases, confirming earlier reports, the case-control differences diminished significantly with increasing TTD (7 days-14 years). Conclusion: Levels of several ULCFAs were lower in incident colorectal cancer cases than controls. However, because case-control differences decreased with increasing TTD, we conclude that these molecules were likely consumed by processes related to cancer progression rather than causal pathways. Impact: ULCFA levels are unlikely to represent exposures that protect individuals from colorectal cancer. Future research should focus on the diagnostic potential and origins of these molecules. Our use of TTD as a covariate in a linear model provides an efficient method for distinguishing causal and reactive biomarkers in biospecimens from prospective cohorts. (C) 2016 AACR.

Association of Multiple Biomarkers of Iron Metabolism and Type 2 Diabetes: The EPIC-InterAct Study

Podmore C., Meidtner K., Schulze M. B., Scott R. A., Ramond A., Butterworth A. S., Di Angelantonio E., Danesh J., Arriola L., Barricarte A., Boeing H., Clavel-Chapelon F., Cross A. J., Dahm C. C., Fagherazzi G., Franks P. W., Gavrila D., Grioni S., Gunter M. J., Gusto G., Jakszyn P., Katzke V., Key T. J., Kuhn T., Mattiello A., Nilsson P. M., Olsen A., Overvad K., Palli D., Quiros J. R., Rolandsson O., Sacerdote C., Sanchez-Cantalejo E., Slimani N., Sluijs I., Spijkerman A. M., Tjonneland A., Tumino R., van der A. Dl, van der Schouw Y. T., Feskens E. J., Forouhi N. G., Sharp S. J., Riboli E., Langenberg C., Wareham N. J.

Diabetes Care; 2016; 39(4): 572-81

PMID:26861925

Abstract as provided by PubMed

OBJECTIVE: Observational studies show an association between ferritin and type 2 diabetes (T2D), suggesting a role of high iron stores in T2D development. However, ferritin is influenced by factors other than iron stores, which is less the case for other biomarkers of iron metabolism. We investigated associations of ferritin, transferrin saturation (TSAT), serum iron, and transferrin with T2D incidence to clarify the role of iron in the pathogenesis of T2D. RESEARCH DESIGN AND METHODS: The European Prospective Investigation into Cancer and Nutrition-InterAct study includes 12,403 incident T2D cases and a representative subcohort of 16,154 individuals from a European cohort with 3.99 million person-years of follow-up. We studied the prospective association of ferritin, TSAT, serum iron, and transferrin with incident T2D in 11,052 cases and a random subcohort of 15,182 individuals and assessed whether these associations differed by subgroups of the population. RESULTS: Higher levels of ferritin and transferrin were associated with a higher risk of T2D (hazard ratio [HR] [95% CI] in men and women, respectively: 1.07 [1.01-1.12] and 1.12 [1.05-1.19] per 100 mug/L higher ferritin level; 1.11 [1.00-1.24] and 1.22 [1.12-1.33] per 0.5 g/L higher transferrin level) after adjustment for age, center, BMI, physical activity, smoking status, education, hs-CRP, alanine aminotransferase, and gamma-glutamyl transferase. Elevated TSAT (>/=45% vs. <45%) was associated with a lower risk of T2D in women (0.68 [0.54-0.86]) but was not statistically significantly associated in men (0.90 [0.75-1.08]). Serum iron was not associated with T2D. The association of ferritin with T2D was stronger among leaner individuals (Pinteraction < 0.01). CONCLUSIONS: The pattern of association of TSAT and transferrin with T2D suggests that the underlying relationship between iron stores and T2D is more complex than the simple link suggested by the association of ferritin with T2D.

The Influence of Hormonal Factors on the Risk of Developing Cervical Cancer and Pre-Cancer: Results from the EPIC Cohort

Roura E., Travier N., Waterboer T., de Sanjose S., Bosch F. X., Pawlita M., Pala V., Weiderpass E., Margall N., Dillner J., Gram I. T., Tjonneland A., Munk C., Palli D., Khaw K. T., Overvad K., Clavel-Chapelon F., Mesrine S., Fournier A., Fortner R. T., Ose J., Steffen A., Trichopoulou A., Lagiou P., Orfanos P., Masala G., Tumino R., Sacerdote C., Polidoro S., Mattiello A., Lund E., Peeters P. H., Bueno-de-Mesquita H. B., Quiros J. R., Sanchez M. J., Navarro C., Barricarte A., Larranaga N., Ekstrom J., Lindquist D., Idahl A., Travis R. C., Merritt M. A., Gunter M. J., Rinaldi S., Tommasino M., Franceschi S., Riboli E., Castellsague X.

PLoS ONE; 2016; 11(1): e0147029

PMID:26808155

Abstract as provided by PubMed

BACKGROUND: In addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC). METHODS AND FINDINGS: We followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. At enrollment, participants completed a questionnaire and provided serum. After a 9-year median follow-up, 261 ICC and 804 CIN3/CIS cases were reported. In a nested case-control study, the sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45,52,58, and antibodies against Chlamydia trachomatis and Human herpesvirus 2. Multivariate analyses were performed to estimate hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI). The cohort analysis showed that number of full-term pregnancies was positively associated with CIN3/CIS risk (p-trend = 0.03). Duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and ICC (HR = 1.6 and HR = 1.8 respectively for >/=15 years versus never use). Ever use of menopausal hormone therapy was associated with a reduced risk of ICC (HR = 0.5, 95%CI: 0.4-0.8). A non-significant reduced risk of ICC with ever use of intrauterine devices (IUD) was found in the nested case-control analysis (OR = 0.6). Analyses restricted to all cases and HPV seropositive controls yielded similar results, revealing a significant inverse association with IUD for combined CIN3/CIS and ICC (OR = 0.7). CONCLUSIONS: Even though HPV is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of CC associated with these hormonal risk factors.

Plasma concentrations and intakes of amino acids in male meat-eaters, fish-eaters, vegetarians and vegans: a cross-sectional analysis in the EPIC-Oxford cohort

Schmidt J. A., Rinaldi S., Scalbert A., Ferrari P., Achaintre D., Gunter M. J., Appleby P. N., Key T. J., Travis R. C.

Eur J Clin Nutr; 2016; 70(3): 306-12

PMID:26395436

Abstract as provided by PubMed

BACKGROUND/OBJECTIVES: We aimed to investigate the differences in plasma concentrations and in intakes of amino acids between male meat-eaters, fish-eaters, vegetarians and vegans in the Oxford arm of the European Prospective Investigation into Cancer and Nutrition. SUBJECTS/METHODS: This cross-sectional analysis included 392 men, aged 30-49 years. Plasma amino acid concentrations were measured with a targeted metabolomic approach using mass spectrometry, and dietary intake was assessed using a food frequency questionnaire. Differences between diet groups in mean plasma concentrations and intakes of amino acids were examined using analysis of variance, controlling for potential confounding factors and multiple testing. RESULTS: In plasma, concentrations of 6 out of 21 amino acids varied significantly by diet group, with differences of -13% to +16% between meat-eaters and vegans. Concentrations of methionine, tryptophan and tyrosine were highest in fish-eaters and vegetarians, followed by meat-eaters, and lowest in vegans. A broadly similar pattern was seen for lysine, whereas alanine concentration was highest in fish-eaters and lowest in meat-eaters. For glycine, vegans had the highest concentration and meat-eaters the lowest. Intakes of all 18 dietary amino acids differed by diet group; for the majority of these, intake was highest in meat-eaters followed by fish-eaters, then vegetarians and lowest in vegans (up to 47% lower than in meat-eaters). CONCLUSIONS: Men belonging to different habitual diet groups have significantly different plasma concentrations of lysine, methionine, tryptophan, alanine, glycine and tyrosine. However, the differences in plasma concentrations were less marked than and did not necessarily mirror those seen for amino acid intakes.

Consumption of soft drinks and juices and risk of liver and biliary tract cancers in a European cohort

Stepien M., Duarte-Salles T., Fedirko V., Trichopoulou A., Lagiou P., Bamia C., Overvad K., Tjonneland A., Hansen L., Boutron-Ruault M. C., Fagherazzi G., Severi G., Kuhn T., Kaaks R., Aleksandrova K., Boeing H., Klinaki E., Palli D., Grioni S., Panico S., Tumino R., Naccarati A., Bueno-de-Mesquita H. B., Peeters P. H., Skeie G., Weiderpass E., Parr C. L., Quiros J. R., Buckland G., Molina-Montes E., Amiano P., Chirlaque M. D., Ardanaz E., Sonestedt E., Ericson U., Wennberg M., Nilsson L. M., Khaw K. T., Wareham N., Bradbury K. E., Ward H. A., Romieu I., Jenab M.

Eur J Nutr; 2016; 55(1): 7-20

PMID:25528243

Abstract as provided by PubMed

PURPOSE: The aim of the study was to assess associations between intake of combined soft drinks (sugar sweetened and artificially sweetened) and fruit and vegetable juices and the risk of hepatocellular carcinoma (HCC), intrahepatic bile duct (IHBC) and biliary tract cancers (GBTC) using data from the European Prospective Investigation into Cancer and Nutrition cohort of 477,206 participants from 10 European countries. METHODS: After 11.4 years of follow-up, 191 HCC, 66 IHBC and 236 GBTC cases were identified. Hazard ratios and 95 % confidence intervals (HR; 95 % CI) were estimated with Cox regression models with multivariable adjustment (baseline total energy intake, alcohol consumption and intake pattern, body mass index, physical activity, level of educational attainment and self-reported diabetes status). RESULTS: No risk associations were observed for IHBC or GBTC. Combined soft drinks consumption of >6 servings/week was positively associated with HCC risk: HR 1.83; 95 % CI 1.11-3.02, p trend = 0.01 versus non-consumers. In sub-group analyses available for 91 % of the cohort artificially sweetened soft drinks increased HCC risk by 6 % per 1 serving increment (HR 1.06, 95 % CI 1.03-1.09, n cases = 101); for sugar-sweetened soft drinks, this association was null (HR 1.00, 95 % CI 0.95-1.06; n cases = 127, p heterogeneity = 0.07). Juice consumption was not associated with HCC risk, except at very low intakes (<1 serving/week: HR 0.60; 95 % CI 0.38-0.95; p trend = 0.02 vs. non-consumers). CONCLUSIONS: Daily intake of combined soft drinks is positively associated with HCC, but a differential association between sugar and artificially sweetened cannot be discounted. This study provides some insight into possible associations of HCC with sugary drinks intake. Further exploration in other settings is required.

A Prospective Evaluation of Early Detection Biomarkers for Ovarian Cancer in the European EPIC Cohort

Terry K. L., Schock H., Fortner R. T., Husing A., Fichorova R. N., Yamamoto H. S., Vitonis A. F., Johnson T., Overvad K., Tjonneland A., Boutron-Ruault M. C., Mesrine S., Severi G., Dossus L., Rinaldi S., Boeing H., Benetou V., Lagiou P., Trichopoulou A., Krogh V., Kuhn E., Panico S., Bueno-de-Mesquita H. B., Onland-Moret N. C., Peeters P. H., Gram I. T., Weiderpass E., Duell E. J., Sanchez M. J., Ardanaz E., Etxezarreta N., Navarro C., Idahl A., Lundin E., Jirstrom K., Manjer J., Wareham N. J., Khaw K. T., Byrne K. S., Travis R. C., Gunter M. J., Merritt M. A., Riboli E., Cramer D. W., Kaaks R.

Clin Cancer Res; 2016; 22(18): 4664-75

PMID:27060155

Abstract as provided by PubMed

PURPOSE: About 60% of ovarian cancers are diagnosed at late stage, when 5-year survival is less than 30% in contrast to 90% for local disease. This has prompted search for early detection biomarkers. For initial testing, specimens taken months or years before ovarian cancer diagnosis are the best source of information to evaluate early detection biomarkers. Here we evaluate the most promising ovarian cancer screening biomarkers in prospectively collected samples from the European Prospective Investigation into Cancer and Nutrition study. EXPERIMENTAL DESIGN: We measured CA125, HE4, CA72.4, and CA15.3 in 810 invasive epithelial ovarian cancer cases and 1,939 controls. We calculated the sensitivity at 95% and 98% specificity as well as area under the receiver operator curve (C-statistic) for each marker individually and in combination. In addition, we evaluated marker performance by stage at diagnosis and time between blood draw and diagnosis. RESULTS: We observed the best discrimination between cases and controls within 6 months of diagnosis for CA125 (C-statistic = 0.92), then HE4 (0.84), CA72.4 (0.77), and CA15.3 (0.73). Marker performance declined with longer time between blood draw and diagnosis and for earlier staged disease. However, assessment of discriminatory ability at early stage was limited by small numbers. Combinations of markers performed modestly, but significantly better than any single marker. CONCLUSIONS: CA125 remains the single best marker for the early detection of invasive epithelial ovarian cancer, but can be slightly improved by combining with other markers. Identifying novel markers for ovarian cancer will require studies including larger numbers of early-stage cases. Clin Cancer Res; 22(18); 4664-75. (c)2016 AACRSee related commentary by Skates, p. 4542.

Pre-diagnostic meat and fibre intakes in relation to colorectal cancer survival in the European Prospective Investigation into Cancer and Nutrition

Ward H. A., Norat T., Overvad K., Dahm C. C., Bueno-de-Mesquita H. B., Jenab M., Fedirko V., van Duijnhoven F. J., Skeie G., Romaguera-Bosch D., Tjonneland A., Olsen A., Carbonnel F., Affret A., Boutron-Ruault M. C., Katzke V., Kuhn T., Aleksandrova K., Boeing H., Trichopoulou A., Lagiou P., Bamia C., Palli D., Sieri S., Tumino R., Naccarati A., Mattiello A., Peeters P. H., Weiderpass E., Asli L. A., Jakszyn P., Ramon Quiros J., Sanchez M. J., Dorronsoro M., Huerta J. M., Barricarte A., Jirstrom K., Ericson U., Johansson I., Gylling B., Bradbury K. E., Khaw K. T., Wareham N. J., Stepien M., Freisling H., Murphy N., Cross A. J., Riboli E.

Br J Nutr; 2016; 116(2): 316-25

PMID:27193442

Abstract as provided by PubMed

Improvements in colorectal cancer (CRC) detection and treatment have led to greater numbers of CRC survivors, for whom there is limited evidence on which to provide dietary guidelines to improve survival outcomes. Higher intake of red and processed meat and lower intake of fibre are associated with greater risk of developing CRC, but there is limited evidence regarding associations with survival after CRC diagnosis. Among 3789 CRC cases in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, pre-diagnostic consumption of red meat, processed meat, poultry and dietary fibre was examined in relation to CRC-specific mortality (n 1008) and all-cause mortality (n 1262) using multivariable Cox regression models, adjusted for CRC risk factors. Pre-diagnostic red meat, processed meat or fibre intakes (defined as quartiles and continuous grams per day) were not associated with CRC-specific or all-cause mortality among CRC survivors; however, a marginal trend across quartiles of processed meat in relation to CRC mortality was detected (P 0.053). Pre-diagnostic poultry intake was inversely associated with all-cause mortality among women (hazard ratio (HR)/20 g/d 0.92; 95 % CI 0.84, 1.00), but not among men (HR 1.00; 95 % CI 0.91, 1.09) (P for heterogeneity=0.10). Pre-diagnostic intake of red meat or fibre is not associated with CRC survival in the EPIC cohort. There is suggestive evidence of an association between poultry intake and all-cause mortality among female CRC survivors and between processed meat intake and CRC-specific mortality; however, further research using post-diagnostic dietary data is required to confirm this relationship.

Urinary excretions of 34 dietary polyphenols and their associations with lifestyle factors in the EPIC cohort study

Zamora-Ros R., Achaintre D., Rothwell J. A., Rinaldi S., Assi N., Ferrari P., Leitzmann M., Boutron-Ruault M. C., Fagherazzi G., Auffret A., Kuhn T., Katzke V., Boeing H., Trichopoulou A., Naska A., Vasilopoulou E., Palli D., Grioni S., Mattiello A., Tumino R., Ricceri F., Slimani N., Romieu I., Scalbert A.

Sci Rep; 2016; 26905

PMID:27273479

Abstract as provided by PubMed

Urinary excretion of 34 dietary polyphenols and their variations according to diet and other lifestyle factors were measured by tandem mass spectrometry in 475 adult participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cross-sectional study. A single 24-hour urine sample was analysed for each subject from 4 European countries. The highest median levels were observed for phenolic acids such as 4-hydroxyphenylacetic acid (157 mumol/24 h), followed by 3-hydroxyphenylacetic, ferulic, vanillic and homovanillic acids (20-50 mumol/24 h). The lowest concentrations were observed for equol, apigenin and resveratrol (<0.1 mumol/24 h). Urinary polyphenols significantly varied by centre, followed by alcohol intake, sex, educational level, and energy intake. This variability is largely explained by geographical variations in the diet, as suggested by the high correlations (r > 0.5) observed between urinary polyphenols and the intake of their main food sources (e.g., resveratrol and gallic acid ethyl ester with red wine intake; caffeic, protocatechuic and ferulic acids with coffee consumption; and hesperetin and naringenin with citrus fruit intake). The large variations in urinary polyphenols observed are largely determined by food preferences. These polyphenol biomarkers should allow more accurate evaluation of the relationships between polyphenol exposure and the risk of chronic diseases in large epidemiological studies.

Dietary polyphenol intake in Europe: the European Prospective Investigation into Cancer and Nutrition (EPIC) study

Zamora-Ros R., Knaze V., Rothwell J. A., Hemon B., Moskal A., Overvad K., Tjonneland A., Kyro C., Fagherazzi G., Boutron-Ruault M. C., Touillaud M., Katzke V., Kuhn T., Boeing H., Forster J., Trichopoulou A., Valanou E., Peppa E., Palli D., Agnoli C., Ricceri F., Tumino R., de Magistris M. S., Peeters P. H., Bueno-de-Mesquita H. B., Engeset D., Skeie G., Hjartaker A., Menendez V., Agudo A., Molina-Montes E., Huerta J. M., Barricarte A., Amiano P., Sonestedt E., Nilsson L. M., Landberg R., Key T. J., Khaw K. T., Wareham N. J., Lu Y., Slimani N., Romieu I., Riboli E., Scalbert A.

Eur J Nutr; 2016; 55(4): 1359-75

PMID:26081647

Abstract as provided by PubMed

BACKGROUND/OBJECTIVES: Polyphenols are plant secondary metabolites with a large variability in their chemical structure and dietary occurrence that have been associated with some protective effects against several chronic diseases. To date, limited data exist on intake of polyphenols in populations. The current cross-sectional analysis aimed at estimating dietary intakes of all currently known individual polyphenols and total intake per class and subclass, and to identify their main food sources in the European Prospective Investigation into Cancer and Nutrition cohort. METHODS: Dietary data at baseline were collected using a standardized 24-h dietary recall software administered to 36,037 adult subjects. Dietary data were linked with Phenol-Explorer, a database with data on 502 individual polyphenols in 452 foods and data on polyphenol losses due to cooking and food processing. RESULTS: Mean total polyphenol intake was the highest in Aarhus-Denmark (1786 mg/day in men and 1626 mg/day in women) and the lowest in Greece (744 mg/day in men and 584 mg/day in women). When dividing the subjects into three regions, the highest intake of total polyphenols was observed in the UK health-conscious group, followed by non-Mediterranean (non-MED) and MED countries. The main polyphenol contributors were phenolic acids (52.5-56.9 %), except in men from MED countries and in the UK health-conscious group where they were flavonoids (49.1-61.7 %). Coffee, tea, and fruits were the most important food sources of total polyphenols. A total of 437 different individual polyphenols were consumed, including 94 consumed at a level >1 mg/day. The most abundant ones were the caffeoylquinic acids and the proanthocyanidin oligomers and polymers. CONCLUSION: This study describes the large number of dietary individual polyphenols consumed and the high variability of their intakes between European populations, particularly between MED and non-MED countries.

Energy and macronutrient intake and risk of differentiated thyroid carcinoma in the European Prospective Investigation into Cancer and Nutrition study

Zamora-Ros R., Rinaldi S., Tsilidis K. K., Weiderpass E., Boutron-Ruault M. C., Rostgaard-Hansen A. L., Tjonneland A., Clavel-Chapelon F., Mesrine S., Katzke V. A., Kuhn T., Forster J., Boeing H., Trichopoulou A., Lagiou P., Klinaki E., Masala G., Sieri S., Ricceri F., Tumino R., Mattiello A., Peeters P. H., Bueno-de-Mesquita H. B., Engeset D., Skeie G., Arguelles M., Agudo A., Sanchez M. J., Chirlaque M. D., Barricarte A., Chamosa S., Almquist M., Tosovic A., Hennings J., Sandstrom M., Schmidt J. A., Khaw K. T., Wareham N. J., Cross A. J., Slimani N., Byrnes G., Romieu I., Riboli E., Franceschi S.

Int J Cancer; 2016; 138(1): 65-73

PMID:26190646

Abstract as provided by PubMed

Incidence rates of differentiated thyroid carcinoma (TC) have increased in many countries. Adiposity and dietary risk factors may play a role, but little is known on the influence of energy intake and macronutrient composition. The aim of this study was to investigate the associations between TC and the intake of energy, macronutrients, glycemic index (GI) and glycemic load in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The study included 477,274 middle-age participants (70.2% women) from ten European countries. Dietary data were collected using country-specific validated dietary questionnaires. Total carbohydrates, proteins, fats, saturated, monounsaturated and polyunsaturated fats (PUFA), starch, sugar, and fiber were computed as g/1,000 kcal. Multivariable Cox regression was used to calculate multivariable adjusted hazard ratios (HR) and 95% confidence interval (CI) by intake quartile (Q). After a mean follow-up time of 11 years, differentiated TC was diagnosed in 556 participants (90% women). Overall, we found significant associations only with total energy (HRQ4 vs .Q1 , 1.29; 95% CI, 1.00-1.68) and PUFA intakes (HRQ4 vs .Q1 , 0.74; 95% CI, 0.57-0.95). However, the associations with starch and sugar intake and GI were significantly heterogeneous across body mass index (BMI) groups, i.e., positive associations with starch and GI were found in participants with a BMI >/= 25 and with sugar intake in those with BMI < 25. Moreover, inverse associations with starch and GI were observed in subjects with BMI < 25. In conclusion, our results suggest that high total energy and low PUFA intakes may increase the risk of differentiated TC. Positive associations with starch intake and GI in participants with BMI >/= 25 suggest that those persons may have a greater insulin response to high starch intake and GI than lean people.

2015

The association of coffee intake with liver cancer risk is mediated by biomarkers of inflammation and hepatocellular injury: data from the European Prospective Investigation into Cancer and Nutrition

Aleksandrova K., Bamia C., Drogan D., Lagiou P., Trichopoulou A., Jenab M., Fedirko V., Romieu I., Bueno-de-Mesquita H. B., Pischon T., Tsilidis K., Overvad K., Tjonneland A., Bouton-Ruault M. C., Dossus L., Racine A., Kaaks R., Kuhn T., Tsironis C., Papatesta E. M., Saitakis G., Palli D., Panico S., Grioni S., Tumino R., Vineis P., Peeters P. H., Weiderpass E., Lukic M., Braaten T., Quiros J. R., Lujan-Barroso L., Sanchez M. J., Chilarque M. D., Ardanas E., Dorronsoro M., Nilsson L. M., Sund M., Wallstrom P., Ohlsson B., Bradbury K. E., Khaw K. T., Wareham N., Stepien M., Duarte-Salles T., Assi N., Murphy N., Gunter M. J., Riboli E., Boeing H., Trichopoulos D.

Am J Clin Nutr; 2015; 102(6): 1498-508

PMID:26561631

Abstract as provided by PubMed

BACKGROUND: Higher coffee intake has been purportedly related to a lower risk of liver cancer. However, it remains unclear whether this association may be accounted for by specific biological mechanisms. OBJECTIVE: We aimed to evaluate the potential mediating roles of inflammatory, metabolic, liver injury, and iron metabolism biomarkers on the association between coffee intake and the primary form of liver cancer-hepatocellular carcinoma (HCC). DESIGN: We conducted a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition among 125 incident HCC cases matched to 250 controls using an incidence-density sampling procedure. The association of coffee intake with HCC risk was evaluated by using multivariable-adjusted conditional logistic regression that accounted for smoking, alcohol consumption, hepatitis infection, and other established liver cancer risk factors. The mediating effects of 21 biomarkers were evaluated on the basis of percentage changes and associated 95% CIs in the estimated regression coefficients of models with and without adjustment for biomarkers individually and in combination. RESULTS: The multivariable-adjusted RR of having >/=4 cups (600 mL) coffee/d compared with <2 cups (300 mL)/d was 0.25 (95% CI: 0.11, 0.62; P-trend = 0.006). A statistically significant attenuation of the association between coffee intake and HCC risk and thereby suspected mediation was confirmed for the inflammatory biomarker IL-6 and for the biomarkers of hepatocellular injury glutamate dehydrogenase, alanine aminotransferase, aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), and total bilirubin, which-in combination-attenuated the regression coefficients by 72% (95% CI: 7%, 239%). Of the investigated biomarkers, IL-6, AST, and GGT produced the highest change in the regression coefficients: 40%, 56%, and 60%, respectively. CONCLUSION: These data suggest that the inverse association of coffee intake with HCC risk was partly accounted for by biomarkers of inflammation and hepatocellular injury.

A prospective study of the immune system activation biomarker neopterin and colorectal cancer risk

Aleksandrova K., Chuang S.C., Boeing H., Zuo H., Tell G.S., Pischon T., Jenab M., Bueno-de-Mesquita B., Vollset S.E., Midttun O., Ueland P.M., Fedirko V., Johansson M., Weiderpass E., Severi G., Racine A., Boutron-Ruault M.C., Kaaks R., Kuhn T., Tjonneland A., Overvad K., Quiros J.R., Jakszyn P., Sanchez M.J., Dorronsoro M., Chirlaque M.D., Ardanaz E., Khaw K.T., Wareham N.J., Travis R.C., Trichopoulou A., Lagiou P., Trichopoulos D., Palli D., Sieri S., Tumino R., Panico S., May A.M., Palmqvist R., Ljuslinder I., Kong S.Y., Freisling H., Gunter M.J., Lu Y., Cross A.J., Riboli E., Vineis P.

J Natl Cancer Inst; 2015; 107(4):

PMID:25713165

Abstract as provided by PubMed

BACKGROUND: Neopterin may be relevant for colorectal cancer (CRC) development, as a biomarker of cellular immune activity exerting pleiotropic effects on cellular ageing, oxidative stress, and inflammation. So far, the association between prediagnostic neopterin and colon and rectal cancer risk has not been evaluated in human populations. METHODS: A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort using data on plasma concentrations of total neopterin (T-N, sum of neopterin and 7,8-dihydroneopterin) in 830 incident CRC case patients (561 colon and 269 rectal) matched within risk sets to 830 control participants. A subsequent replication study used data from the Hordaland Health Study, where 173 CRC case patients have been diagnosed among 6594 healthy participants over 12 years of follow-up. RESULTS: After multivariable adjustment for a priori chosen CRC risk factors, a "U-shaped" association of T-N with CRC was revealed. Compared with the second quintile of the T-N distribution, the relative risks for the first, third, fourth, and fifth quintiles were 2.37 (95% CI = 1.66 to 3.39), 1.24 (95% CI = 0.87 to 1.77), 1.55 (95% CI = 1.08 to 2.22), and 2.31 (95% CI = 1.63 to 3.27), respectively. Replication of these associations within the Hordaland Health Study yielded similar results. No differences have been observed when the associations were explored by colon and rectal cancer site (two-sided P difference = .87) and after excluding case patients diagnosed within the first four follow-up years. CONCLUSIONS: These novel findings provide evidence of the role of both suppressed and activated cell-mediated immunity as reflected by prediagnostic T-N concentrations in the development of CRC

A statistical framework to model the meeting-in-the-middle principle using metabolomic data: application to hepatocellular carcinoma in the EPIC study

Assi N., Fages A., Vineis P., Chadeau-Hyam M., Stepien M., Duarte-Salles T., Byrnes G., Boumaza H., Knuppel S., Kuhn T., Palli D., Bamia C., Boshuizen H., Bonet C., Overvad K., Johansson M., Travis R., Gunter M. J., Lund E., Dossus L., Elena-Herrmann B., Riboli E., Jenab M., Viallon V., Ferrari P.

Mutagenesis; 2015; 30(6): 743-53

PMID:26130468

Abstract as provided by PubMed

Metabolomics is a potentially powerful tool for identification of biomarkers associated with lifestyle exposures and risk of various diseases. This is the rationale of the 'meeting-in-the-middle' concept, for which an analytical framework was developed in this study. In a nested case-control study on hepatocellular carcinoma (HCC) within the European Prospective Investigation into Cancer and nutrition (EPIC), serum (1)H nuclear magnetic resonance (NMR) spectra (800 MHz) were acquired for 114 cases and 222 matched controls. Through partial least square (PLS) analysis, 21 lifestyle variables (the 'predictors', including information on diet, anthropometry and clinical characteristics) were linked to a set of 285 metabolic variables (the 'responses'). The three resulting scores were related to HCC risk by means of conditional logistic regressions. The first PLS factor was not associated with HCC risk. The second PLS metabolomic factor was positively associated with tyrosine and glucose, and was related to a significantly increased HCC risk with OR = 1.11 (95% CI: 1.02, 1.22, P = 0.02) for a 1SD change in the responses score, and a similar association was found for the corresponding lifestyle component of the factor. The third PLS lifestyle factor was associated with lifetime alcohol consumption, hepatitis and smoking, and had negative loadings on vegetables intake. Its metabolomic counterpart displayed positive loadings on ethanol, glutamate and phenylalanine. These factors were positively and statistically significantly associated with HCC risk, with 1.37 (1.05, 1.79, P = 0.02) and 1.22 (1.04, 1.44, P = 0.01), respectively. Evidence of mediation was found in both the second and third PLS factors, where the metabolomic signals mediated the relation between the lifestyle component and HCC outcome. This study devised a way to bridge lifestyle variables to HCC risk through NMR metabolomics data. This implementation of the 'meeting-in-the-middle' approach finds natural applications in settings characterised by high-dimensional data, increasingly frequent in the omics generation.

Fruit and vegetable consumption in relation to hepatocellular carcinoma in a multi-centre, European cohort study

Bamia C., Lagiou P., Jenab M., Aleksandrova K., Fedirko V., Trichopoulos D., Overvad K., Tjonneland A., Olsen A., Clavel-Chapelon F., Boutron-Ruault M.C., Kvaskoff M., Katzke V.A., Kuhn T., Boeing H., Nothlings U., Palli D., Sieri S., Panico S., Tumino R., Naccarati A., Bueno-de-Mesquita H.A., Peeters P.H., Weiderpass E., Skeie G., Quiros J.R., Agudo A., Chirlaque M.D., Sanchez M.J., Ardanaz E., Dorronsoro M., Ericson U., Nilsson L.M., Wennberg M., Khaw K.T., Wareham N., Key T.J., Travis R.C., Ferrari P., Stepien M., Duarte-Salles T., Norat T., Murphy N., Riboli E., Trichopoulou A.

Br J Cancer; 2015; 112(7): 1273-1282

PMID:25742480

Abstract as provided by PubMed

BACKGROUND: Vegetable and/or fruit intakes in association with hepatocellular carcinoma (HCC) risk have been investigated in case-control studies conducted in specific European countries and cohort studies conducted in Asia, with inconclusive results. No multi-centre European cohort has investigated the indicated associations. METHODS: In 486 799 men/women from the European Prospective Investigation into Cancer and nutrition, we identified 201 HCC cases after 11 years median follow-up. We calculated adjusted hazard ratios (HRs) for HCC incidence for sex-specific quintiles and per 100 g d(-1) increments of vegetable/fruit intakes. RESULTS: Higher vegetable intake was associated with a statistically significant, monotonic reduction of HCC risk: HR (100 g d(-1) increment): 0.83; 95% CI: 0.71-0.98. This association was consistent in sensitivity analyses with no apparent heterogeneity across strata of HCC risk factors. Fruit intake was not associated with HCC incidence: HR (100 g d(-1) increment): 1.01; 95% CI: 0.92-1.11. CONCLUSIONS: Vegetable, but not fruit, intake is associated with lower HCC risk with no evidence for heterogeneity of this association in strata of important HCC risk factors. Mechanistic studies should clarify pathways underlying this association. Given that HCC prognosis is poor and that vegetables are practically universally accessible, our results may be important, especially for those at high risk for the disease

Coffee, tea and decaffeinated coffee in relation to hepatocellular carcinoma in a European population: Multicentre, prospective cohort study

Bamia C., Lagiou P., Jenab M., Trichopoulou A., Fedirko V., Aleksandrova K., Pischon T., Overvad K., Olsen A., Tjonneland A., Boutron-Ruault M.C., Fagherazzi G., Racine A., Kuhn T., Boeing H., Floegel A., Benetou V., Palli D., Grioni S., Panico S., Tumino R., Vineis P., Bueno-de-Mesquita H.B., Dik V.K., Bhoo-Pathy N., Uiterwaal C.S., Weiderpass E., Lund E., Quiros J.R., Zamora-Ros R., Molina-Montes E., Chirlaque M.D., Ardanaz E., Dorronsoro M., Lindkvist B., Wallstrom P., Nilsson L.M., Sund M., Khaw K.T., Wareham N., Bradbury K.E., Travis R.C., Ferrari P., Duarte-Salles T., Stepien M., Gunter M., Murphy N., Riboli E., Trichopoulos D.

Int. J. Cancer; 2015; 136(8): 1899-1908

PMID:25219573

Abstract as provided by PubMed

Inverse associations of coffee and/or tea in relation to hepatocellular carcinoma (HCC) risk have been consistently identified in studies conducted mostly in Asia where consumption patterns of such beverages differ from Europe. In the European Prospective Investigation into Cancer and nutrition (EPIC), we identified 201 HCC cases among 486,799 men/women, after a median follow-up of 11 years. We calculated adjusted hazard ratios (HRs) for HCC incidence in relation to quintiles/categories of coffee/tea intakes. We found that increased coffee and tea intakes were consistently associated with lower HCC risk. The inverse associations were substantial, monotonic and statistically significant. Coffee consumers in the highest compared to the lowest quintile had lower HCC risk by 72% [HR: 0.28; 95% confidence intervals (CIs): 0.16-0.50, p-trend < 0.001]. The corresponding association of tea with HCC risk was 0.41 (95% CI: 0.22-0.78, p-trend = 0.003). There was no compelling evidence of heterogeneity of these associations across strata of important HCC risk factors, including hepatitis B or hepatitis C status (available in a nested case-control study). The inverse, monotonic associations of coffee intake with HCC were apparent for caffeinated (p-trend = 0.009), but not decaffeinated (p-trend = 0.45) coffee for which, however, data were available for a fraction of subjects. Results from this multicentre, European cohort study strengthen the existing evidence regarding the inverse association between coffee/tea and HCC risk. Given the apparent lack of heterogeneity of these associations by HCC risk factors and that coffee/tea are universal exposures, our results could have important implications for high HCC risk subjects

Reproductive factors and epithelial ovarian cancer survival in the EPIC cohort study

Besevic J., Gunter M. J., Fortner R. T., Tsilidis K. K., Weiderpass E., Charlotte Onland-Moret N., Dossus L., Tjonneland A., Hansen L., Overvad K., Mesrine S., Baglietto L., Clavel-Chapelon F., Kaaks R., Aleksandrova K., Boeing H., Trichopoulou A., Lagiou P., Bamia C., Masala G., Agnoli C., Tumino R., Ricceri F., Panico S., Bueno-de-Mesquita H. A., Peeters P. H., Jareid M., Ramon Quiros J., Duell E. J., Sanchez M. J., Larranaga N., Chirlaque M. D., Barricarte A., Dias J. A., Sonestedt E., Idahl A., Lundin E., Wareham N. J., Khaw K. T., Travis R. C., Rinaldi S., Romieu I., Riboli E., Merritt M. A.

Br J Cancer; 2015; 113(11): 1622-31

PMID:26554655

Abstract as provided by PubMed

BACKGROUND: Reproductive factors influence the risk of developing epithelial ovarian cancer (EOC), but little is known about their association with survival. We tested whether prediagnostic reproductive factors influenced EOC-specific survival among 1025 invasive EOC cases identified in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which included 521 330 total participants (approximately 370 000 women) aged 25-70 years at recruitment from 1992 to 2000. METHODS: Information on reproductive characteristics was collected at recruitment. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), and multivariable models were adjusted for age and year of diagnosis, body mass index, tumour stage, smoking status and stratified by study centre. RESULTS: After a mean follow-up of 3.6 years (+/-3.2 s.d.) following EOC diagnosis, 511 (49.9%) of the 1025 women died from EOC. We observed a suggestive survival advantage in menopausal hormone therapy (MHT) users (ever vs never use, HR=0.80, 95% CI=0.62-1.03) and a significant survival benefit in long-term MHT users (5 years use vs never use, HR=0.70, 95% CI=0.50-0.99, Ptrend=0.04). We observed similar results for MHT use when restricting to serous cases. Other reproductive factors, including parity, breastfeeding, oral contraceptive use and age at menarche or menopause, were not associated with EOC-specific mortality risk. CONCLUSIONS: Further studies are warranted to investigate the possible improvement in EOC survival in MHT users.

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