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The Association of Gastric Cancer Risk with Plasma Folate, Cobalamin, and Methylenetetrahydrofolate Reductase Polymorphisms in the European Prospective Investigation into Cancer and Nutrition

¹ LOCUS for Homocysteine and Related Vitamins, Institutes of Medicine and Public Health and Primary Health Care, University of Bergen, and Haukeland University Hospital; ² UNIFOB-Helse, Bergen, Norway; ³ IARC, Lyon, France; ⁴ The Norwegian Institute of Public Health, Oslo, Norway; ⁵ Department of Epidemiology, IDIBELL-Catalan Institute of Oncology; ⁶ Translational Research Laboratory, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain; ⁷ IRIS Research Center, Chiron-Vaccines, Siena, Italy; ⁸ Molecular and Nutritional Epidemiology Unit, Centro per lo Studio e la Prevenzione Oncologica, Scientific Institute of Tuscany, Florence, Italy; ⁹ Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Germany; ¹⁰ Center for Nutrition and Health, National Institute for Public Health and the Environment, Bilthoven, the Netherlands; ¹¹ Institute of Pathology and Molecular Immunology of the University of Porto and Medical Faculty/H.S. Joao, Porto, Portugal; ¹² Nutritional Epidemiology Unit, National Cancer Institute, Milan, Italy; ¹³ Department of Epidemiology and Public Health, Imperial College, London, United Kingdom; ¹⁴ Department of Biomedical Science, University of Torino, Turin, Italy; ¹⁵ Cancer Registry Azienda Ospedaliera Civile-M.P. Arezzo, Ragusa, Italy; ¹⁶ Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy; ¹⁷ Department of Medicine, Lund University; ¹⁸ Department of Surgery, University Hospital, Malmö, Sweden; ¹⁹ Department of Medical Biosciences, Pathology and ²⁰ Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden; ²¹ Andalusian School of Public Health, Granada, Spain; ²² Department of Public Health of Guipuzkoa, San Sebastian, Spain; ²³ Public Health Institute, Navarra, Spain; ²⁴ Department of Epidemiology, Health Council of Murcia, Murcia, Spain; ²⁵ Public Health and Health Planning Directorate, Asturias, Spain (Dirección General de Salud Pública, Consejería de Salud y Servicios Sanitarios, Asturias, Spain); ²⁶ Cancer Research UK, Epidemiology Unit, University of Oxford, Oxford, United Kingdom; ²⁷ MRC Dunn Human Nutrition Unit and MRC Centre for Nutritional Epidemiology in Cancer Prevention and Survival, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; ²⁸ Division of Clinical Epidemiology, German Cancer Research Center, Heidelberg, Germany; ²⁹ Department of Clinical Epidemiology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark; ³⁰ Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; ³¹ Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands; ³² Institut National de la Santé et de la Recherche Médicale, U521, Institut Gustave Roussy, Villejuif, France; ³³ Department of Hygiene and Epidemiology, Medical School University of Athens, Athens, Greece; and ³⁴ Institute of Community Medicine, University of Tromsø, Tromsø, Norway

Requests for reprints: Stein Emil Vollset, Institute of Public Health and Primary Health Care, University of Bergen, Kalfarveien 31, 5093 Bergen, Norway. E-mail: vollset{at}uib.no

Previous studies have shown inconsistent associations of folate intake and polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene with gastric cancer risk. Our nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort is the first prospective study of blood folate levels and gastric cancer. Gastric cancer cases (n = 247) and controls (n = 631) were matched for study center, age, sex, and time of blood donation. Two common single nucleotide polymorphisms of the MTHFR gene were determined, as were plasma concentrations of folate, cobalamin (vitamin B12), total homocysteine, and methylmalonic acid (cobalamin deficiency marker) in prediagnostic plasma. Risk measures were calculated with conditional logistic regression. Although no relations were observed between plasma folate or total homocysteine concentrations and gastric cancer, we observed a trend toward lower risk of gastric cancer with increasing cobalamin concentrations (odds ratio, 0.79 per SD increase in cobalamin; P = 0.01). Further analyses showed that the inverse association between cobalamin and gastric cancer was confined to cancer cases with low pepsinogen A levels (marker of severe chronic atrophic gastritis) at the time of blood sampling. The 677 CT MTHFR polymorphism was not associated with gastric cancer, but we observed an increased risk with the variant genotype of the 1298 AC polymorphism (odds ratio, 1.47 for CC versus AA; P = 0.04). In conclusion, we found no evidence of a role of folate in gastric cancer etiology. However, we observed increased gastric cancer risk at low cobalamin levels that was most likely due to compromised cobalamin status in atrophic gastritis preceding gastric cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2416–24)

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