From Medscape Medical News
Jacquelyn K. Beals, PhD
January 19, 2010 — A questionnaire on food intake combined with an analysis of DNA from the sputum of smokers shows that intake of leafy green vegetables, folate, and multivitamins protects smokers against the methylation of several genes often silenced in lung cancer. Methylation, the addition of methyl groups to cytosine bases of DNA, prevents a gene from being transcribed, essentially blocking its function.
Published in the January 15 issue of Cancer Research, this study leads to new conceptions of lung cancer prevention based on the influence of diet on the epigenome of patients' respiratory epithelium.
Although lung cancer most frequently results from the carcinogenic effects of tobacco, changes leading to cancer occur over the course of several decades. The 8 genes analyzed in this study are frequently "turned off" in lung cancer by promoter methylation, associated in previous studies with greater risk of developing the disease. Thus, higher methylation levels are associated with increased risk.
Of these 8 genes, 7 "are tumor suppressor genes, and the eighth is a gene involved in DNA repair," said senior author Steven A. Belinsky, PhD, director of the Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, in his email to Medscape Oncology. "Most notably, one of the genes is p16, a critical gene for regulating cell cycle control."
Participants were drawn from the Lovelace Smokers Cohort. Cohort members are former and current smokers between 40 and 75 years old with at least 15 pack-years of smoking history. Individuals from the cohort filled out the Harvard University Food Frequency Questionnaire Dietary Assessment form to indicate their intake frequency of approximately 150 food items. After excluding individuals with caloric intakes exceeding sex-specific ranges, 1101 participants remained.
Foods with established or suspected connections with methylation or lung cancer were considered most carefully. The assessments included animal fat; vitamins C, E, and B9 (folate), among others; alcohol; cod liver oil; and multivitamins. Foods analyzed included 6 groups of potential relevance: yellow vegetables, leafy green vegetables (a major source of folate), cruciferous vegetables, tomatoes, fruit, and red or processed meats. The hypothesis was that animal fat and red and processed meats would be associated with greater methylation, whereas fruit, vegetable, and vitamin intake would be associated with lower methylation status.
The 8 genes — p16, MGMT, DAPK, RASSF1A, PAX5α, PAX5β, GATA4, and GATA5 — had previously established associations with the risk for lung cancer. DNA was obtained from cells isolated from each participant's sputum samples, and polymerase chain reaction was used to identify methylated forms of the genes of interest. Patients were "scored" by the number of methylated genes and were grouped into those having fewer than 2 genes methylated (low) and those with 2 or more genes methylated (high).
Significant Links Between Methylation Status and Dietary Variables
Statistical analysis found significant associations between methylation status and specific dietary variables. Intake of leafy green vegetables was associated with decreased risk for high methylation (odds ratio [OR], .84; 95% confidence interval [CI], .74 - .93; P < .001). Folate intake yielded similar results (OR, .84; 95% CI, .72 - .99; P = .04). Even current multivitamin use was significantly associated with methylation status: current use (OR, .57; 95% CI, .40 - .83; P = .01).
"There was a dose response with consumption of vegetables and sustained vitamin use, and increased duration was associated with better protection," observed Dr. Belinsky. "Multivitamins and leafy green vegetables have things other than folate, although that is the common link, and...the amount of folate varies by multivitamin and vegetable, so I don't know that there is a simple yes or no answer [regarding dose dependence]," he said.
The report summarizes their findings: "Green leafy vegetables were the only food item in this analysis to exhibit protection against methylation status." In addition, the use of multivitamins, which supply many of the same substances as leafy green vegetables, had a significant protective effect.
Should all smokers be told to increase their intake of spinach and kale? "Our findings certainly support yes for smokers," said Dr. Belinsky. "Most cancers arise through inactivating genes by methylation, so I don't think consumption of leafy green vegetables and a multivitamin would do anything negative, and it could help." He noted, however, that further studies are needed to validate their findings.
"Adequate folate intake is essential, because folate is a crucial cofactor in one-carbon metabolism and has an important role in DNA synthesis and replication," said Margaret R. Spitz, MD, MPH, clinical professor of epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, in her email replying to Medscape Oncology's request for independent commentary. "Also remember that folate deficiency is associated with...an established risk factor for cardiovascular disease.
"I do not think we can make any clinical recommendations yet," said Dr. Spitz. With folate-fortified foods in the United States, many adults achieve their recommended allowance of folate from those sources alone. Nevertheless, "All smokers should be advised to quit, and everyone should follow common-sense dietary principles," Dr. Spitz concluded.
Dr. Belinsky is a consultant and has licensed intellectual property with Oncomethylome Sciences. Dr. Spitz has disclosed no relevant financial relationships.
Cancer Res. 2010;70(2):568-574. Abstract
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