Several folate-related biomarkers were associated with self-reported physician-diagnosed lung cancer in a cross-sectional analysis of US adults, although the findings do not establish whether folate status contributes to lung cancer development, results from cancer-related metabolic changes, or reflects other confounding factors.
Researchers analyzed data from the National Health and Nutrition Examination Survey collected from 2007 to 2018. The analysis included 27,631 adults aged 20 years and older, including 67 patients with lung cancer. Following 1:2 propensity score matching for age, race, body mass index, marital status, hypertension, diabetes, smoking status, and alcohol use, the matched cohort included 201 patients.
Among patients with lung cancer, 90% met the study definition for smoking history of more than 100 lifetime cigarettes. However, the matching analysis adjusted only for smoking status and did not account for smoking intensity, pack-years, or current vs former smoking status.
The researchers evaluated serum and dietary folate measures including total folate, folic acid, dietary folate, serum folate, red blood cell folate, 5-methylTHF, unmetabolized folic acid, 5-formylTHF, tetrahydrofolate, 5,10-methenylTHF, and MeFox. Data for tetrahydrofolate, 5-formylTHF, 5,10-methenylTHF, unmetabolized folic acid, and MeFox were available only from 2011 to 2018, limiting the sample size for those analyses further.
Following matching, total folate, dietary folate, 5-formylTHF, and 5,10-methenylTHF were statistically significantly associated with lung cancer status. Patients with lung cancer had lower median total folate and dietary folate levels compared with matched controls, whereas 5-formylTHF and 5,10-methenylTHF levels were higher among patients with lung cancer.
Restricted cubic spline analyses suggested that some associations varied by biomarker concentration. Total folate demonstrated a positive association with lung cancer prevalence at lower concentrations, particularly below 284.8 µg, with the strongest association observed below 189 µg. For 5,10-methenylTHF, lung cancer prevalence increased at concentrations above 0.14 nmol/L. Folic acid concentrations below 107.6 µg and red blood cell folate concentrations between 1,175 and 1,623.9 nmol/L were also associated with higher lung cancer prevalence within specific concentration ranges.
The researchers noted that folate may exert both protective and tumor-promoting effects through pathways involving nucleotide synthesis, DNA methylation, DNA repair, and immune regulation. However, the cross-sectional design substantially limits interpretation of the findings. Patients with lung cancer may have altered dietary intake, absorption, metabolism, supplement use, or treatment-related changes that affect folate biomarkers independent of any causal relationship.
The study was additionally limited by the small number of patients with lung cancer, reliance on self-reported physician diagnosis, lack of information on cancer stage or treatment, and absence of adjustment for factors such as vitamin B12 status or genetic variation in folate metabolism. The researchers also evaluated 11 folate-related biomarkers without adjustment for multiple comparisons, raising the possibility that some statistically significant findings may have occurred by chance.
“Our study delineates a nuanced relationship between folate status and [lung cancer], influenced by metabolic derivatives, exposure duration, and population characteristics,” wrote lead study researcher Binbin Li, of Shandong University of Traditional Chinese Medicine, and colleagues. The researchers added that the findings “caution against simplistic interpretations of folate supplementation.”
The researchers reported no competing interests.
Source: BMC Pulmonary Medicine
