Relationships among folate, alcohol consumption, gene variants in one-carbon metabolism and p16INK4a methylation and expression in healthy breast tissues

Carcinogenesis. 2015 Jan;36(1):60-7. doi: 10.1093/carcin/bgu219. Epub 2014 Oct 24.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Alcohol Drinking / adverse effects*
  • Breast / drug effects
  • Breast / metabolism*
  • Cross-Sectional Studies
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • DNA Methylation*
  • Female
  • Ferredoxin-NADP Reductase / genetics*
  • Folic Acid / metabolism*
  • Follow-Up Studies
  • Humans
  • Methylenetetrahydrofolate Dehydrogenase (NADP) / genetics*
  • Minor Histocompatibility Antigens
  • Prognosis
  • Promoter Regions, Genetic / genetics

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • Minor Histocompatibility Antigens
  • Folic Acid
  • methionine synthase reductase
  • Ferredoxin-NADP Reductase
  • MTHFD1 protein, human
  • Methylenetetrahydrofolate Dehydrogenase (NADP)