Introduction Lung cancer (LC) remains the leading cause of cancer mortality worldwide. In addition to tobacco exposure, low intake of specific micronutrient has been linked to LC. The diet is the main source of vitamins and amino acids involved in the one-carbon metabolism, which is considered key mechanism in maintaining DNA integrity, regulating gene expression, and may thus affect carcinogenesis. Two important branches of the one-carbon metabolism are implicated in cancer: DNA methylation (MET) and nucleotide synthesis (NS). In addition, immune activation (IA) is involved in the ageing process in normal healthy individuals and in a number of pathologies, including cancer.

Methods To investigate the three pathways and their relationships with LC, we applied structural equation models to relate three latent variables corresponding to each mechanism to LC status, controlling for independent effects of tobacco exposure (plasma cotinine). Each latent variable represents one of the mechanisms: MET (methionine, cobalamin, folate and serine), NS (folate, serine, vitamin B₆, and Riboflavin) and IA (vitamin B₆, Kynurenine/tryptophan ratio and Neopterin). The analysis was conducted using a data set from a nested case-control from the European Prospective Investigation into Cancer and Nutrition cohort.

Results We have found a direct and protective effect for MET (p=0.011) and IA (p=0.006), meanwhile NS presented only an indirect protective effect (p=0.012).

Conclusion In conclusion, our results support the roles for MET and IA in LC aetiology, whereas the factor representing NS also showed some weak indirect associations. Tobacco remains the predominant predictive factor for LC.