Context  B vitamins and factors related to 1-carbon metabolism help to maintain DNA integrity and regulate gene expression and may affect cancer risk.

Objective  To investigate if 1-carbon metabolism factors are associated with onset of lung cancer.

Design, Setting, and Participants  The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 519 978 participants from 10 countries between 1992 and 2000, of whom 385 747 donated blood. By 2006, 899 lung cancer cases wereidentified and 1770 control participants were individually matched by country, sex, date of birth, and date of blood collection. Serum levels were measured for 6 factors of 1-carbon metabolism and cotinine.

Main Outcome Measure  Odds ratios (ORs) of lung cancer by serum levels of 4 B vitamins (B2, B6, folate [B9], and B12), methionine, and homocysteine.

Results  Within the entire EPIC cohort, the age-standardized incidence rates of lung cancer (standardized to the world population, aged 35-79 years) were 6.6, 44.9, and 156.1 per 100 000 person-years among never, former, and current smokers for men,respectively. The corresponding incidence rates for women were 7.1, 23.9, and 100.9 per 100 000 person-years, respectively. After accounting for smoking, a lower risk for lung cancer was seen for elevated serum levels of B6 (fourth vs first quartile OR, 0.44; 95% confidence interval [CI], 0.33-0.60; P for trend <.000001), as well as for serum methionine (fourth vs first quartile OR, 0.52; 95% CI, 0.39-0.69; P for trend <.000001). Similar and consistent decreases in risk were observed in never, former, and current smokers, indicating that results were not due to confounding by smoking. The magnitude of risk was also constant with increasing length of follow-up, indicating that the associations were not explained by preclinical disease. A lower risk was also seen for serum folate (fourth vs first quartile OR, 0.68; 95% CI, 0.51-0.90; P for trend = .001), although this was apparent only for former and current smokers. When participants were classified by median levels of serum methionine and B6, having above-median levels of both was associated with a lower lung cancer risk overall (OR, 0.41; 95% CI, 0.31-0.54), as well as separately among never (OR, 0.36; 95% CI, 0.18-0.72), former (OR, 0.51; 95% CI, 0.34-0.76), and current smokers (OR, 0.42; 95% CI, 0.27-0.65).

Conclusion  Serum levels of vitamin B6 and methionine were inversely associated with risk of lung cancer.

Author Affiliations: International Agency for Research on Cancer (IARC), Lyon, France (Drs Johansson, Slimani, Boffetta, Jenab, and Brennan); Institute for Ageing and Health, Newcastle University, Newcastle, United Kingdom (Dr Relton); Section for Pharmacology, Institute of Medicine, University of Bergen, and Laboratory of Clinical Biochemistry, Haukeland University Hospital (Dr Ueland), Bergen, Norway; Department of Public Health and Primary Health Care, University of Bergen, and Division of Epidemiology, Norwegian Institute of Public Health (Dr Vollset), Bergen, Norway; Bevital AS, Bergen, Norway (Dr Midttun); Department of Heart Disease, Haukeland University Hospital, and Section for Cardiology, Institute of Medicine, University of Bergen (Dr Nygård) Bergen, Norway; INSERM ERI20 (Institut National de la Santé et de la Recherche Médicale), ERI20, Institut Gustave Roussy, and Paris South University (Drs Clavel-Chapelon, Boutron-Ruault, and Fagherazzi), Villejuif, France; Divisions of Cancer Epidemiology (Dr Kaaks), and Clinical Epidemiology (Dr Rohrmann), German Cancer Research Centre, Heidelberg, Germany; Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany(Dr Boeing and Weikert); National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands (Dr Bueno-de-Mesquita and Ms Ros); Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands (Ms Ros); Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands (Drs van Gils and Peeters); Faculty of Medicine, Imperial College, London, United Kingdom (Dr Peeters); Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain (Dr Agudo); Public Health Institute of Navarra, Pamplona, Spain (Dr Barricarte); CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain (Drs Barricarte, Navarro, Sánchez, and Larrañaga); Department of Epidemiology, Regional Council of Health and Consumer Affairs, Murcia, Spain (Dr Navarro); Public Health and Participation Directorate, Health and Health Care Services Council, Asturias, Spain (Dr Rodríguez); Andalusian School of Public Health, Granada, Spain (Dr Sánchez); Public Health Division of Gipuzkoa, Basque Government, Donostia-San Sebastian, Spain (Dr Larrañaga); Department of Gerontology, Department of Public Health and Primary Care, University of Cambridge (Dr Khaw), and MRC Epidemiology Unit, Strangeways Research Laboratory (Dr Wareham) Cambridge, United Kingdom; Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom (Drs Allen and Crowe); Division of Epidemiology, and Public Health and Primary Care, Imperial College, London, United Kingdom (Drs Gallo, Norat, Riboli, and Vineis); MRC/HPA Centre for Environment and Health, Imperial College, London, United Kingdom (Dr Vineis); Epidemiology Unit, National Cancer Institute, Milan, Italy (Dr Krogh); Molecular and Nutritional Epidemiology Unit, ISPO -Cancer Research and Prevention Institute, Florence, Italy (Dr Masala); Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy (Dr Panico); Center for Cancer Prevention (CPO-Piemonte), and Human Genetic Foundation (HuGeF), Torino, Italy (Dr Sacerdote); Cancer Registry, Azienda Ospedaliera "Civile MP Arezzo," Ragusa, Italy (Dr Tumino); WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece (Drs Trichopoulou and Lagiou); Hellenic Health Foundation, Athens, Greece (Drs Trichopoulou); Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, Massachusetts (Drs Lagiou and Trichopoulos); Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece (Dr Trichopoulos); Departments of Radiation Sciences, Oncology (Dr Rasmuson), Public Health and Clinical Medicine, Nutritional Research (Dr Hallmans), and Nutritional Research (Dr Vineis), Umeå University, Umeå, Sweden; MRC/HPA Centre for Environment and Health, Imperial College, London, United Kingdom, and ISI Foundation, Torino, Italy (Dr Vineis).

Mattias Johansson, PhD ; Caroline Relton, PhD; Per Magne Ueland, MD, PhD; Stein Emil Vollset, MD, DrPH; Øivind Midttun, PhD; Ottar Nygård, MD, PhD; Nadia Slimani, PhD; Paolo Boffetta, MD, PhD; Mazda Jenab, PhD; Françoise Clavel- Chapelon, PhD;Marie-Christine Boutron-Ruault, MD, PhD; Guy Fagherazzi, MSc; Rudolf Kaaks, PhD; Sabine Rohrmann, PhD; Heiner Boeing, PhD; Cornelia Weikert, MD, PhD; H. Bas Bueno- de-Mesquita, MD, MPH, PhD; Martine M. Ros, MSc; Carla H. van Gils, PhD;Petra H. M. Peeters, MD, PhD; Antonio Agudo, MD, MSc, PhD; Aurelio Barricarte, MD, PhD; Carmen Navarro, MD, MSc, PhD; Laudina Rodríguez, MD; Maria-José Sánchez, MD, PhD; Nerea Larrañaga, MD, MSc; Kay-Tee Khaw, FRCP;Nick Wareham, FRCP, PhD, MSc; Naomi E. Allen, PhD; Francesca Crowe, PhD; Valentina Gallo, MD, PhD; Teresa Norat, PhD; Vittorio Krogh, MD; Giovanna Masala, MD, PhD; Salvatore Panico, MD, MSc; Carlotta Sacerdote, MD, PhD; Rosario Tumino, MD, MSc;Antonia Trichopoulou, MD, PhD; Pagona Lagiou, MD, PhD; Dimitrios Trichopoulos, MD, PhD; Torgny Rasmuson, MD, PhD; Göran Hallmans, MD, PhD; Elio Riboli, MD, MPH, ScM; Paolo Vineis, MD, MPH, FFPH; Paul Brennan, PhD 

JAMA. 2010;303(23):2377-2385.