One-carbon metabolism biomarkers and risk of urothelial cell carcinoma in the European prospective investigation into cancer and nutrition.

Published associations between dietary folate and bladder cancer risk are inconsistent. Biomarkers may provide more accurate measures of nutrient status. This nested case-control analysis within the European Prospective Investigation into Cancer and Nutrition (EPIC) investigated associations between pre-diagnostic serum folate, homocysteine, vitamins B6 and B12 and the risk of urothelial cell carcinomas of the bladder (UCC). A total of 824 patients with newly diagnosed UCC were matched with 824 cohort members. Serum folate, homocysteine, and vitamins B6 and B12 were measured. Odds ratios (OR) and 95% confidence intervals (CI) for total, aggressive, and non-aggressive UCC were estimated using conditional logistic regression with adjustment for smoking status, smoking duration and intensity, and other potential confounders. Additionally, statistical interaction with smoking status was assessed. A halving in serum folate concentrations was moderately associated with risk of UCC (OR: 1.18; 95% CI: 0.98-1.43), in particular aggressive UCC (OR: 1.34; 95% CI: 1.02-1.75; p-heterogeneity = 0.19). Compared to never smokers in the highest quartile of folate concentrations, this association seemed only apparent among current smokers in the lowest quartile of folate concentrations (OR: 6.26; 95% CI: 3.62-10.81, p-interaction = 0.07). Dietary folate was not associated with aggressive UCC (OR: 1.26; 95% CI: 0.81-1.95; p-heterogeneity = 0.14). No association was observed between serum homocysteine, vitamins B6 and B12 and risk of UCC. This study suggests that lower serum folate concentrations are associated with increased UCC risk, in particular aggressive UCC. Residual confounding by smoking cannot be ruled out and these findings require confirmation in future studies with multiple measurements.

International journal of cancer. 2019 Jan 29 [Epub ahead of print]

Alina Vrieling, H Bas Bueno-De-Mesquita, Martine M Ros, Ellen Kampman, Katja K Aben, Frederike L Büchner, Eugène H Jansen, Nina Roswall, Anne Tjønneland, Marie-Christine Boutron-Ruault, Claire Cadeau, Jenny Chang-Claude, Rudolf Kaaks, Steffen Weikert, Heiner Boeing, Antonia Trichopoulou, Pagona Lagiou, Dimitrios Trichopoulos, Sabina Sieri, Domenico Palli, Salvatore Panico, Petra H Peeters, Elisabete Weiderpass, Guri Skeie, Paula Jakszyn, María-Dolores Chirlaque, Eva Ardanaz, María-José Sánchez, Roy Ehrnström, Johan Malm, Börje Ljungberg, Kay-Tee Khaw, Nick J Wareham, Paul Brennan, Mattias Johansson, Elio Riboli, Lambertus A Kiemeney

Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands., National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands., Danish Cancer Society Research Center, Copenhagen, Denmark., Inserm, Center for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health team, Villejuif, France., Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Germany., Department of Epidemiology, German Institute of Human Nutrition, Nuthetal, Germany., WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics University of Athens Medical School, Athens, Greece., Hellenic Health Foundation, Athens, Greece., Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Molecular and Nutritional Epidemiology Unit, Cancer and Prevention Institute (ISPO), Florence, Italy., Department of Clinical and Experimental Medicine, Federico II University, Medical School, Naples, Italy., Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, United Kingdom., Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Artic University of Norway, Tromsø, Norway., Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology (ICO), Barcelona, Spain., Consortium for Biomedical Research in Epidemiology and Public Health (CIBER de Epidemiologia y Salud Pública), Madrid, Spain., Laboratory Medicine, Department of Pathology, Skåne University Hospital Malmö, Malmö, Sweden., Department of Translational Medicine, Division of Clinical Chemistry, Lund University, Malmö, Sweden., Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden., Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom., MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom., Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France.