High Red Blood Folate Levels Linked to Silenced Tumor-Suppressors

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People with higher levels of folate in their red blood cells were more likely to have two cancer-preventing genes shut down by methylation -- a chemical off switch for genes, researchers report this week in the December issue of Cancer Prevention Research.

DNA hypermethylation, notes co-author Jean-Pierre Issa, M.D., professor in MD Anderson's Department of Leukemia, is found in a variety of cancers and diseases of aging. Methyl groups attach to genes, protruding like tags, preventing gene expression.

"Our new finding is that having high levels of folate in the blood as observed in a sensitive measure of red blood cell (RBC) folate is related to higher levels of DNA methylation," Issa says.

Folate is a natural B vitamin that plays a role in DNA creation, repair and function, as well as red blood cell production. Pregnant women who have a folate deficiency are at elevated risk of having a child with neural tube defects, which occur when the spinal cord or brain fail to fully close.

Folate's found in leafy vegetables, fruits, dried beans and peas. Since 1998 its synthetic version, folic acid, has been added to breads, cereals, flours, pastas, rice and other grain products under order from the U.S. Food and Drug Administration, reducing the rate of neural tube defects in the United States.  

The recommended daily requirement is 400 micrograms for adult men and women from a balanced diet and an additional 400 for women capable of becoming pregnant. Folate also is taken as a dietary supplement.

Folate's effect on cancer, once thought to be mainly preventive, has become less clear in recent years, with scientists finding cancer-promoting aspects of folate intake in colorectal and other cancers.

The research team analyzed the association between folate blood levels and dietary and lifestyle factors on DNA methylation in normal colorectal tissue. They enrolled 781 patients from a parent clinical trial that compared folate to aspirin in the prevention of precancerous colorectal polyps.

The genes, ERα and SFRP1, are expressed in normal colorectal tissue but silenced by methylation in colon cancer. They also have been found to be methylated in breast, prostate and lung tumors.

Age was strongly associated with increased methylation -- a finding that confirmed longstanding research. Neither folate nor aspirin treatment had a significant effect. However, RBC folate was associated with methylation of both genes with significant differences emerging between the top quarter of patients with the highest RBC folate count and the bottom quarter with the lowest. RBC folate levels closely reflect long-term folate intake.

"These differences were not trivial. They were the equivalent of 10 years of extra aging for those with high RBC folate counts," Issa says.
"Today, it's worrisome that taking extra folate over the long term might lead to more DNA methylation, which then might lead to extra diseases including potentially an increased chance of developing cancer and other diseases of aging," Issa says.

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