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.
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.
Carcinogenesis. 2015 Jan;36(1):60-7. doi: 10.1093/carcin/bgu219. Epub 2014 Oct 24.
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.
p16（INK4a）是一种肿瘤抑制基因，在乳腺癌中经常发生过度甲基化；这种 p16（INK4a）的表观遗传沉默发生在癌变的早期。p16（INK4a）甲基化的危险因素和功能后果尚不清楚。饮酒是乳腺癌的一个危险因素，它会阻碍叶酸代谢，从而可能改变基因甲基化，因为叶酸在 DNA 甲基化中起着关键作用。在一项对 138 名没有乳腺癌病史的女性进行乳房缩小术的横断面研究中，我们研究了乳腺癌的危险因素、血浆和乳房叶酸浓度、一碳代谢基因的变异、p16（INK4a）启动子甲基化和 P16 蛋白表达。使用逻辑回归估计多变量调整后的比值比（OR）和 95%置信区间（CI）。p16（INK4a）甲基化与 P16 表达呈负相关（r = -0.28；P = 0.002）。饮酒与较低的乳房叶酸有关（P = 0.03）、更高的 p16（INK4a）启动子甲基化（P = 0.007）和较低的 P16 表达（P = 0.002）。较高的乳房叶酸浓度与较低的 p16（INK4a）启动子甲基化有关（P = 0.06）。MTRR（rs1801394）和 MTHFD1（rs1950902）的遗传变异与较高的 p16（INK4a）启动子甲基化有关（OR = 2.66，95%CI：1.11-6.42 和 OR = 2.72，95%CI：1.12-6.66），而 TYMS（rs502396）的变异与 P16 蛋白表达较低有关（OR = 0.22，95%CI：0.05-0.99）。鉴于这是第一项表明饮酒、乳房叶酸和一碳代谢基因的变异与健康组织中的 p16（INK4a）启动子甲基化和 P16 蛋白表达有关的研究；这些发现需要复制。
