Relationships among folate, alcohol consumption, gene variants in one-carbon metabolism and p16 INK4a methylation and expression in healthy breast tissues

• Published in: Carcinogenesis (New York) 2014-10, Vol.36 (1), p.60-67
• Main Authors: Llanos, Adana A., Dumitrescu, Ramona G., Brasky, Theodore M., Liu, Zhenhua, Mason, Joel B., Marian, Catalin, Makambi, Kepher H., Spear, Scott L., Kallakury, Bhaskar V.S., Freudenheim, Jo L., Shields, Peter G.
• Format: Article
• Language: English
• Subjects: Original Manuscript
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgu219

Alcohol consumption, breast folate concentration and variation in one-carbon metabolism genes may be determinants of p16 INK4a promoter methylation and P16 protein expression in histologically normal breast tissues, and may influence early breast carcinogenic events. 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.