Skip to main content
ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #340998

Title: Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues

item LLANO, ADANA - Rutgers University
item MARIAN, CATALIN - The Ohio State University
item BRASKY, THEODORE - The Ohio State University
item DUMITRESCU, RAMONA - Distilled Spirits Council Of The United States
item LIU, ZHENHUA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item MASON, JOEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item MAKAMBI, KEPHER - Georgetown University
item SPEARS, SCOTT - Georgetown University
item KALLAKURY, BHASKAR - Georgetown University
item FREUDENHEIM, JO - University Of Buffalo
item SHIELDS, PETER - The Ohio State University

Submitted to: Epigenetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/9/2015
Publication Date: 6/20/2015
Citation: Llano, A.A., Marian, C., Brasky, T.M., Dumitrescu, R.G., Liu, Z., Mason, J.B., Makambi, K.H., Spears, S.L., Kallakury, B.V., Freudenheim, J.L., Shields, P.G. 2015. Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues. Epigenetics. 10(8):727-735.

Interpretive Summary: A common event on the molecular level that precedes the appearance of most cancers is the loss of small chemical compounds called "methyl groups" on the DNA of the affected tissue; thus, undermethylation of DNA is considered to be a marker of a predisposition to cancer. The B-vitamin, folate, is the supplier of these methyl groups, and under certain experimental conditions, a lack of the vitamin leads to a depletion of methyl groups attached to DNA (so-called "DNA hypomethylation.") We examined the concentrations of the vitamin folate in the breasts of 121 women who had undergone breast reduction surgery and determined the amount of DNA methylation in the breast tissue. There was no correlation between the concentration of folate in the breast and the extent of DNA methylation, but genetic variants in the enzyme systems that process folate were linked to the extent of DNA methylation. We conclude that genetically-based variations in folate metabolism may determine the extent of DNA methylation and therefore determine cancer risk, in part, in the human breast.

Technical Abstract: Genome-wide DNA hypomethylation is an early event in the carcinogenic process. Percent methylation of long interspersed nucleotide element-1 (LINE-1) is a biomarker of genome-wide methylation and is a potential biomarker for breast cancer. Understanding factors associated with percent LINE-1 DNA methylation in histologically normal tissues could provide insight into early stages of carcinogenesis. In a cross-sectional study of 121 healthy women with no prior history of cancer who underwent reduction mammoplasty, we examined associations between plasma and breast folate, genetic variation in one-carbon metabolism, and percent LINE-1 methylation using multivariable regression models (adjusting for race, oral contraceptive use, and alcohol use). Results are expressed as the ratio of LINE-1 methylation relative to that of the referent group, with the corresponding 95% confidence intervals (CI). We found no significant associations between plasma or breast folate and percent LINE-1 methylation. Variation in MTHFR, MTR, and MTRR were significantly associated with percent LINE-1 methylation. Variant allele carriers of MTHFR A1289C had 4% lower LINE-1 methylation (Ratio 0.96, 95% CI 0.93-0.98), while variant allele carriers of MTR A2756G (Ratio 1.03, 95% CI 1.01-1.06) and MTRR A66G (Ratio 1.03, 95% CI 1.01-1.06) had 3% higher LINE-1 methylation, compared to those carrying the more common genotypes of these SNPs. DNA methylation of LINE-1 elements in histologically normal breast tissues is influenced by polymorphisms in genes in the one-carbon metabolism pathway. Future studies are needed to investigate the sociodemographic, environmental, and additional genetic determinants of DNA methylation in breast tissues and their impact on breast cancer susceptibility.