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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #354024
Title: Genetic variation in one-carbon metabolism in relation to genome-wide DNA methylation in breast tissue from healthy women

Author
item SONG, MIN-AE - The Ohio State University
item BRASKY, THEODORE - The Ohio State University
item CATALIN, MARIAN - The Ohio State University
item WENG, DANIEL - The Ohio State University
item TASLIM, CENNY - The Ohio State University
item LLANOS, ADANA - Rutgers University
item DUMITRESCU, RAMONA - Distilled Spirits Council Of The United States
item LIU, ZHENHUA - University Of Massachusetts
item MASON, JOEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item SPEAR, SCOTT - Georgetown University
item KALLAKURY, BHASKAR - Georgetown University
item FREUDENHEIM, JO - University Of Buffalo
item SHIELDS, PETER - The Ohio State University

Submitted to: Carcinogenesis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/6/2016
Publication Date: 3/28/2016
Citation: Song, M., Brasky, T.M., Catalin, M., Weng, D.Y., Taslim, C., Llanos, A.A., Dumitrescu, R.G., Liu, Z., Mason, J.B., Spear, S.L., Kallakury, B.V., Freudenheim, J.L., Shields, P.G. 2016. Genetic variation in one-carbon metabolism in relation to genome-wide DNA methylation in breast tissue from healthy women. Carcinogenesis. 37(5):471-480. https://doi.org/10.1093/carcin/bgw030.
DOI: https://doi.org/10.1093/carcin/bgw030

Interpretive Summary: Evidence indicates that certain lifestyle factors, such as habitual alcohol consumption, increase the risk of developing breast cancer. Also, increased dietary intake of the B-vitamin, folate, is believed to diminish the risk of breast cancer, particularly in women who are moderate or heavy consumers of alcohol. The effects of both these factors are thought to be mediated by altering a regulatory element in genes called "gene methylation." The complex inter-relationship by which alcohol and folate consumption interact alters gene methylation and the risk of breast cancer and may be further modified by common genetic variations in the genes that control the metabolism of folate. We therefore studied common variants in folate metabolism genes, gene methylation, habitual alcohol consumption, and folate concentrations in breast tissues obtained at the time of elective breast reduction surgery in 81 healthy, cancer-free women. Eight gene variants in folate metabolism genes were found to be associated with alterations in the methylation of that gene. Also, changes in gene methylation in several genes were associated with alcohol consumption and breast folate levels. This is the first comprehensive study of the association between gene variants in folate metabolism genes and gene methylation in normal breast tissues. These gene variants, as well as alcohol intake and folate exposure, appear to affect gene methylation in breast tissues of healthy women. These observations provide some initial understanding of how alcohol intake and folate exposure might collectively determine the risk of developing breast cancer.

Technical Abstract: Single-nucleotide polymorphisms (SNPs) in one-carbon metabolism genes and lifestyle factors (alcohol drinking and breast folate) may be determinants of whole-genome methylation in the breast. DNA methylation profiling was performed using the Illumina Infinium HumanMethylation450 BeadChip in 81 normal breast tissues from women undergoing reduction mammoplasty and no history of cancer. ANCOVA, adjusting for age, race and body mass index, was used to identify differentially methylated (DM) CpGs. Gene expression, by the Affymetrix GeneChip Human Transcriptome Array 2.0, was correlated with DM. Biological networks of DM genes were assigned using Ingenuity Pathway Analysis. Fifty-seven CpG sites (CpGs) were DM in association with eight SNPs in FTHFD, MTHFD1, MTHFR, MTR, MTRR and TYMS (P < 5.0 x 10^-5); 56% of the DM CpGs were associated with FTHFD SNPs, including DM within FTHFD. Gene expression was negatively correlated with FTHFD methylation (r = -0.25, P = 0.017). Four DM CpGs identified by SNPs in MTRR, MTHFR and FTHFD were significantly associated with alcohol consumption and/or breast folate. The top biological network of DM CpGs was associated with Energy Production, Molecular Transportation, and Nucleic Acid Metabolism. This is the first comprehensive study of the association between SNPs in one-carbon metabolism genes and genome-wide DNA methylation in normal breast tissues. These SNPs, especially FTHFD, as well as alcohol intake and folate exposure, appear to affect DM in breast tissues of healthy women. The finding that SNPs in FTHFD and MTR are associated with their own methylation is novel and highlights a role for these SNPs as methylation quantitative trait loci.