title: Relationships among folate, alcohol consumption, gene variants in one-carbon metabolism and p16INK4a methylation and expression in healthy breast tissues.
abstract: p16(INK4a) is a tumor suppressor gene, frequently hypermethylated in breast cancer; this epigenetic silencing of p16(INK4a) occurs early in carcinogenesis. The risk factors and functional consequences of p16(INK4a) methylation are unknown. Alcohol consumption, a breast cancer risk factor, impedes folate metabolism and may thereby alter gene methylation since folate plays a pivotal role in DNA methylation. In a cross-sectional study of 138 women with no history of breast cancer who underwent reduction mammoplasty, we studied breast cancer risk factors, plasma and breast folate concentrations, variation in one-carbon metabolism genes, p16(INK4a) promoter methylation and P16 protein expression. Logistic regression was used to estimate multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI). p16(INK4a) methylation was negatively correlated with P16 expression (r = -0.28; P = 0.002). Alcohol consumption was associated with lower breast folate (P = 0.03), higher p16(INK4a) promoter methylation (P = 0.007) and less P16 expression (P = 0.002). Higher breast folate concentrations were associated with lower p16(INK4a) promoter methylation (P = 0.06). Genetic variation in MTRR (rs1801394) and MTHFD1 (rs1950902) was associated with higher p16 (INK4a) promoter methylation (OR = 2.66, 95% CI: 1.11-6.42 and OR = 2.72, 95% CI: 1.12-6.66, respectively), whereas variation in TYMS (rs502396) was associated with less P16 protein expression (OR = 0.22, 95% CI: 0.05-0.99). Given that this is the first study to indicate that alcohol consumption, breast folate and variation in one-carbon metabolism genes are associated with p16(INK4a) promoter methylation and P16 protein expression in healthy tissues; these findings require replication.
authors.affiliation: Division of Population Sciences, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43201, USA, Department of Epidemiology, RBHS-School of Public Health and Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08903, USA.
authors.forename: Adana A
authors.initials: AA
authors.lastname: Llanos
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA, Department of Medical Genetics and Epidemiology, Basic Sciences Program, Saba University School of Medicine, Saba, Dutch Caribbean, The Netherlands.
authors.forename: Ramona G
authors.initials: RG
authors.lastname: Dumitrescu
authors.affiliation: Division of Cancer Prevention and Control, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Brasky
authors.affiliation: Human Nutrition Research Center, Tufts University, Boston, MA 02111, USA, Department of Nutrition, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Human Nutrition Research Center, Tufts University, Boston, MA 02111, USA.
authors.forename: Joel B
authors.initials: JB
authors.lastname: Mason
authors.affiliation: Division of Cancer Prevention and Control, College of Medicine, The Ohio State University, Columbus, OH 43210, USA, Department of Biochemistry and Pharmacology, University of Medicine and Pharmacy Timisoara, Timisoara, Romania.
authors.forename: Catalin
authors.initials: C
authors.lastname: Marian
authors.affiliation: Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown University, Washington, DC 20057, USA.
authors.forename: Kepher H
authors.initials: KH
authors.lastname: Makambi
authors.affiliation: Department of Plastic Surgery, Georgetown University, Washington, DC 20057, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Spear
authors.affiliation: Department of Pathology, Georgetown University, Washington, DC 20057, USA and.
authors.forename: Bhaskar V S
authors.initials: BV
authors.lastname: Kallakury
authors.affiliation: Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Jo L
authors.initials: JL
authors.lastname: Freudenheim
authors.affiliation: Division of Cancer Prevention and Control, College of Medicine, The Ohio State University, Columbus, OH 43210, USA, peter.shields@osumc.edu.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Shields
mesh_terms: D000328:Adult; D000428:Alcohol Drinking / Q000009:adverse effects*; D001940:Breast / Q000187:drug effects / Q000378:metabolism*; D003430:Cross-Sectional Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D005492:Folic Acid / Q000378:metabolism*; D005500:Follow-Up Studies; D006801:Humans; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics*; D015778:Minor Histocompatibility Antigens; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D015778:Minor Histocompatibility Antigens; D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP)