• Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France; Department of Epidemiology and Biostatistics, Imperial College London, London, UK; Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA; Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA; Epidemiology Research Program, American Cancer Society, Inc., Atlanta, GA; Division of Cancer Epidemiology and Genetics and Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA; Health Promotion Sciences, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ; Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN; International Epidemiology Institute, Rockville, MD; Departments of Obstetrics and Gynecology, Population Health and Environmental Medicine and Population Health, New York University School of Medicine, New York, NY; Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI; Channing Division of Network Medicine, Division of Preventive Medicine, and Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Epidemiology and Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA; Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia; Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation, Torino, Italy; Inserm (Institut National de la Sante et de la Recherche Medicale), Centre for Research in Epidemiology and Population Health, Villejuif, France; Umeå, University, Umeå, Sweden; HUNT Research Centre, Department of Public Health and General Practice, NTNU, Norwegian University of Science and Technology, Levanger, Norway; Department of Epidemiology, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai, China; Duke-NUS Graduate Medical School Singapore, Singapore; Department of Epidemiology, George W Comstock Center for Public Health Research and Prevention Health Monitoring Unit, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD; Laboratory of Clinical Biochemistry, Department of Clinical Science, University of Bergen, Bergen, Norway; Haukeland University Hospital, Bergen, Norway; Bevital AS, Bergen, Norway; Boston VA Medical Center, Boston, MA; Department of Surgery, Skåne University Hospital Malmö, Lund University, Malmö, Sweden; Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden; Institute of Genetic Medicine, Newcastle University, Newcastle, UK; MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.

BACKGROUND: Circulating concentrations of B vitamins and factors related to one-carbon metabolism have been found to be strongly inversely associated with lung cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The extent to which these associations are present in other study populations is unknown.

METHODS: Within 20 prospective cohorts from the National Cancer Institute Cohort Consortium, a nested case-control study was designed including 5364 incident lung cancer case patients and 5364 control subjects who were individually matched to case patients by age, sex, cohort, and smoking status. Centralized biochemical analyses were performed to measure circulating concentrations of vitamin B6, folate, and methionine, as well as cotinine as an indicator of recent tobacco exposure. The association between these biomarkers and lung cancer risk was evaluated using conditional logistic regression models.

RESULTS: Participants with higher circulating concentrations of vitamin B6 and folate had a modestly decreased risk of lung cancer risk overall, the odds ratios when comparing the top and bottom fourths (OR 4vs1 ) being 0.88 (95% confidence interval [CI] = 0.78 to 1.00) and 0.86 (95% CI = 0.74 to 0.99), respectively. We found stronger associations among men (vitamin B6: OR 4vs1 = 0.74, 95% CI = 0.62 to 0.89; folate: OR 4vs1 = 0.75, 95% CI = 0.61 to 0.93) and ever smokers (vitamin B6: OR 4vs1 = 0.78, 95% CI = 0.67 to 0.91; folate: OR 4vs1 = 0.87, 95% CI = 0.73 to 1.03). We further noted that the association of folate was restricted to Europe/Australia and Asia, whereas no clear association was observed for the United States. Circulating concentrations of methionine were not associated with lung cancer risk overall or in important subgroups.

CONCLUSIONS: Although confounding by tobacco exposure or reverse causation cannot be ruled out, these study results are compatible with a small decrease in lung cancer risk in ever smokers who avoid low concentrations of circulating folate and vitamin B6.