Evaluating the protective effect of folate against lung cancer in a large European prospective study

  • Topic: Lung cancer
  • Institution: International Agency for Research on Cancer (IARC)
  • Country: France
  • Status: Completed

Scientific abstract

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B‐vitamins and factors related to one‐carbon metabolism help to maintain DNA integrity and regulate gene expression, and may affect cancer risk.


To investigate if one‐carbon metabolism factors are associated with onset of lung cancer.

Design, Setting & Participants

The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 519,978 participants from ten countries between 1992 and 2000, of whom 385,747 donated blood. By 2006, 899 lung cancer cases were identified and 1,770 controls were individually matched by country, sex, date of birth and date of blood collection. Serum levels were measured for six one‐carbon metabolism factors as well as cotinine.

Main Outcome Measure

Odds ratios of lung cancer by serum levels of four B‐vitamins (B2, B6, folate and B12), methionine and homocysteine.


Within the entire EPIC cohort the age standardised incidence rates of lung cancer (standardised to the world population, aged 35‐79) were 6.6, 44.9 and 156.1/100,000 person years (pyrs) among never, former, and current smokers for men, respectively. The corresponding incidence rates for women were 7.1, 23.9, and 100.9/100,000 pyrs, respectively. After accounting for smoking, a lower risk for lung cancer was seen for elevated serum levels of B6 (odds ratio of 4th vs 1st quartile [OR4v1] = 0.44; 95% confidence interval [95% CI], 0.33‐0.60; p for trend [ptrend]< 0.000001), as well as for serum methionine (OR4v1=0.52; 95% CI, 0.39‐0.69; ptrend<0.000001). 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 pre‐clinical disease. A lower risk was also seen for serum folate, (OR4v1=0.68; 95% CI, 0.51‐0.90; ptrend=0.001), 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 resulted in a substantially 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, 0.18‐0.71), former (OR=0.51; 95% CI, 0.34‐0.76), and current smokers (OR=0.42; 95% CI, 0.27‐0.65).


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

Plain language abstract


B‐vitamins and related enzymes are involved in a pathway labeled one‐carbon metabolism, which is important for maintaining DNA stability and regulating gene activity. We therefore wanted to investigate if circulating B‐vitamins as measured in blood are related to risk of developing lung cancer.


In the US over 225,000 lung cancer cases are diagnosed every year representing approximately 15% of all new cancer cases, and 28% of cancer deaths. The only current option for lung cancer prevention is through avoidance of exposure to lung carcinogens, in particular tobacco smoking. It has been hypothesised that deficiencies in B‐vitamins may increase the probability of DNA damage and influence gene regulation. Low blood levels of B‐vitamins could therefore increase risk of cancer development, and specific factors have previously been investigated in relation to various cancers. Because it is possible to increase blood levels of specific B‐vitamin through dietary intake of specific foods, it may be possible to modify cancer risk through dietary changes. Major sources of one carbon nutrients and related vitamins are varied and include fruits and green leafy vegetables (folate/vitamin B9), fortified cereals and whole grains (vitamin B6), as well as meat and dairy products (vitamin B12). The main focus of B‐vitamins and cancer prevention up to now has been on folate (vitamin B9) and colorectal cancer, but few studies have investigated B‐vitamins in relation to lung cancer.


We measured blood levels of six B‐vitamins and related one‐carbon factors in order to compare approximately 900 lung cancer cases and 1800 healthy controls. The blood samples were drawn several years before diagnosis and originated in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which includes participants from ten European countries.

Key findings

We found the blood concentrations of vitamin B6 and methionine were substantially lower in lung cancer cases than in controls. The results were independent of tobacco smoking, indicating that increasing levels of both vitamin B6 and methionine protects against lung cancer. The magnitude of the protective effects were high enough to exclude the possibility of chance as an explanation for the findings.

Grant publications