Leafy green vegetables, folate, and some multivitamins could serve
as protective factors against lung cancer in current and former
smokers, according to a study that is a first step in understanding a
complex association. The study was supported by the National Cancer
Institute (NCI), part of the National Institutes of Health. The study
appeared online Jan. 12, 2010, in Cancer Research.
Researchers, led by Steven Belinsky, Ph.D., Lovelace Respiratory Research
Institute, Albuquerque, N.M., examined cells that were coughed up by current
and former smokers. Upon careful study of the cells and by comparing those
cells with profiles of smokers' dietary intake of leafy green vegetables, folate,
and some multivitamins, they found that those particular substances could influence
the prevalence of cellular gene methylation. Gene methylation is a chemical
modification used by the cell to control gene expression.
The addition of methyl groups, which are simple four-atom molecules,
to DNA can affect whether the gene is expressed, i.e., whether the
gene’s signal to produce a protein is actually sent. Many genes
involved in critical cell functions, including cell division, are
methylated in lung tumors. As seen in previous studies, gene
methylation is likely to be a major mechanism in lung cancer
development and progression, as well as a potential marker for the
early detection of lung cancer.
In the study, slightly more than 1,100 current and former smokers
from the Lovelace Smokers Cohort submitted sputum samples and completed
questionnaires regarding their dietary intake. Most (75 percent) of the
participants were women who had been enrolled in the study since 2001.
Men were not enrolled until 2004.
The researchers analyzed cells in the sputum samples for the
methylation status of eight genes that were linked to increased risk
for lung cancer in previous studies. Two of the genes, p16 and MGMT,
have been found to be highly associated with increased methylation
The researchers next investigated associations between 21 dietary
variables and methylation. Both higher intake of leafy green vegetables
and higher intake of folate were significantly associated with a
reduced probability of high methylation. Current multivitamin users
also had less DNA methylation, although there was no association
between the duration of multivitamin use and methylation.
"Aberrant gene methylation is a known mechanism in the development of
cancer from cigarette smoke carcinogens," said
Jacob Kagan, Ph.D., of the Cancer Biomarkers Research Group in NCI's Division
of Cancer Prevention.
There has been considerable debate regarding the relationship between
diet and cancer prevention. Previous studies, such as the
Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Trial, showed
an increased risk of lung cancer in smokers who took beta-carotene
supplements. In contrast, the current study shows reduced gene
methylation with the intake of multivitamin supplements that are rich
in phytochemicals, such as vitamin C, carotenoids, lutein, folic acid,
and vitamins A and K — the same agents present in leafy greens.
Previous studies have suggested an association between a low folate
intake and increased lung cancer risk in current and former smokers.
Higher folate intake has been associated with lower methylation of
genes in colorectal tumors as well.
"Additional research is needed to independently validate the current
observations, and also to help resolve contradictions between varying
studies. This particular study used a well-planned design and can serve
as a basis for future identification of the mechanistic targets of
these dietary factors. Such studies are important steps for the future
success of chemopreventive strategies" said Sudhir Srivastava, Ph.D.,
chief, Biomarkers Research Group, NCI.
The authors of this study believe that since gene methylation is a
promising marker for lung cancer, understanding the factors underlying
methylation is a high priority and could be used for early detection
and chemoprevention of lung cancer. They also recommend that lung
cancer prevention interventions be developed that take into
consideration the influence of dietary factors on cancer risk.
NCI leads the National Cancer Program and the NIH effort to
dramatically reduce the burden of cancer and improve the lives of
cancer patients and their families, through research into prevention
and cancer biology, the development of new interventions, and the
training and mentoring of new researchers. For more information about
cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).