Previous studies have suggested that components of one-carbon metabolism, particularly circulating vitamin B6, have an etiological role in renal cell carcinoma (RCC). Vitamin B6 is a cofactor in the transsulfuration pathway. We sought to holistically investigate the role of the transsulfuration pathway in RCC risk. We conducted a nested case-control study (455 RCC cases and 455 matched controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Plasma samples from the baseline visit were analyzed for metabolites of the transsulfuration pathway, including pyridoxal 5'-phosphate (PLP, the biologically active form of vitamin B6), homocysteine, serine, cystathionine, and cysteine, in addition to folate. Bayesian conditional logistic regression was used to estimate associations of metabolites with RCC risk as well as interactions with established RCC risk factors. Circulating PLP and cysteine were inversely associated with RCC risk, and these association were not attenuated after adjustment for other transsulfuration metabolites (odds ratio (OR) and 90% credible interval (CrI) per 1 SD increase in log concentration: 0.76 [0.66, 0.87]; 0.81 [0.66, 0.96], respectively). A comparison of joint metabolite profiles suggested substantially greater RCC risk for the profile representative of low overall transsulfuration function compared with high function (OR 2.70 [90% CrI 1.26, 5.70]). We found some statistical evidence of interactions of cysteine with body mass index, and PLP and homocysteine with smoking status, on their associations with RCC risk. In conclusion, we found evidence suggesting that the transsulfuration pathway may play a role in metabolic dysregulation leading to RCC development. This article is protected by copyright. All rights reserved.
International journal of cancer. 2022 Apr 02 [Epub ahead of print]
Joanna L Clasen, Alicia K Heath, Heleen Van Puyvelde, Inge Huybrechts, Jin Young Park, Pietro Ferrari, Ghislaine Scelo, Arve Ulvik, Øivind Midttun, Per Magne Ueland, Kim Overvad, Anne Kirstine Eriksen, Anne Tjønneland, Rudolf Kaaks, Verena Katzke, Matthias B Schulze, Domenico Palli, Claudia Agnoli, Paolo Chiodini, Rosario Tumino, Carlotta Sacerdote, Raul Zamora-Ros, Miguel Rodriguez-Barranco, Carmen Santiuste, Eva Ardanaz, Pilar Amiano, Julie A Schmidt, Elisabete Weiderpass, Marc Gunter, Elio Riboli, Amanda J Cross, Mattias Johansson, David C Muller
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK., International Agency for Research on Cancer, Lyon, France., Cancer Epidemiology Unit, University of Turin, Turin, Italy., Bevital A/S, Bergen, Norway., Department of Public Health, Aarhus University, Bartholins Allé 2, DK-8000 Aarhus C, Denmark., Danish Cancer Society Research Center, Diet, Genes and Environment, Strandboulevarden 49, DK-2100, Copenhagen., Division of Cancer Epidemiology, German Cancer research Center (DKFZ), Heidelberg, Germany., Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany., Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy., Epidemiology and Prevention Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori Via Venezian., Dipartimento di Salute Mentale e Fisica e Medicina Preventiva, Università degli Studi della Campania 'Luigi Vanvitelli'., Hyblean Association for Epidemiological Research (AIRE -ONLUS), Ragusa, Italy., Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital, Via Santena 7, 10126, Turin, Italy., Unit of Nutrition and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain., Escuela Andaluza de Salud Pública (EASP), Granada, Spain., Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain., Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.