title: Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues.
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 the impact on breast cancer susceptibility.
authors.affiliation: a Department of Epidemiology; Rutgers School of Public Health and the Rutgers Cancer Institute of New Jersey ; New Brunswick , NJ USA.
authors.forename: Adana A M
authors.initials: AA
authors.lastname: Llanos
authors.forename: Catalin
authors.initials: C
authors.lastname: Marian
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Brasky
authors.forename: Ramona G
authors.initials: RG
authors.lastname: Dumitrescu
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Liu
authors.forename: Joel B
authors.initials: JB
authors.lastname: Mason
authors.forename: Kepher H
authors.initials: KH
authors.lastname: Makambi
authors.forename: Scott L
authors.initials: SL
authors.lastname: Spear
authors.forename: Bhaskar V S
authors.initials: BV
authors.lastname: Kallakury
authors.forename: Jo L
authors.initials: JL
authors.lastname: Freudenheim
authors.forename: Peter G
authors.initials: PG
authors.lastname: Shields
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics*; D000328:Adult; D000483:Alleles; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002244:Carbon / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D005492:Folic Acid / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D002244:Carbon; D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; C585801:MTR protein, human
keywords: LINE-1 methylation; breast tissues; folate; genome-wide methylation; one-carbon metabolism