Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Carcinogenesis. 2014 Feb;35(2):333-8. doi: 10.1093/carcin/bgt342. Epub 2013 Oct 15.
Global decrease in DNA methylation is a common feature of cancer and is associated with genomic and chromosomal instability. Retrospective case-control studies have reported that cancer patients have lower global methylation levels in blood DNA than do controls. We used prospectively collected samples and a case-cohort study design to examine global DNA methylation and incident breast cancer in 294 cases and a sample of 646 non-cases in the Sister Study, a study of 50 884 women aged 35-74 years who had not been diagnosed with breast cancer at the time of blood draw. Global methylation in DNA from peripheral blood was assessed by pyrosequencing of the LINE-1 repetitive element. Quartiles of LINE-1 methylation levels were associated with the risk of breast cancer in a dose-dependent fashion (P, trend = 0.002), with an increased risk observed among women in the lowest quartile compared with those in the highest quartile (hazard ratio = 1.75; 95% confidence interval 1.19, 2.59). We also examined 22 polymorphisms in 10 one-carbon metabolism genes in relation to both LINE-1 methylation levels and breast cancer. We found three single-nucleotide polymorphisms in those genes associated with LINE-1 methylation: SLC19A1 (rs1051266); MTRR (rs10380) and MTHFR (rs1537514), one of which was also associated with breast cancer risk: MTHFR (rs1537514). PON1 (rs757158) was associated with breast cancer but not methylation.
全球 DNA 甲基化水平降低是癌症的一个常见特征，与基因组和染色体不稳定性有关。回顾性病例对照研究报告称，癌症患者的血液 DNA 中全球甲基化水平低于对照组。我们使用前瞻性收集的样本和病例对照研究设计，在 Sister 研究中检查了 294 例病例和 646 例非病例的全基因组 DNA 甲基化与乳腺癌的发病情况。通过对 LINE-1 重复元件进行焦磷酸测序来评估外周血 DNA 的整体甲基化水平。LINE-1 甲基化水平的四分位数与乳腺癌风险呈剂量依赖性（P，趋势=0.002），与最高四分位数相比，最低四分位数的女性患乳腺癌的风险增加（危险比=1.75；95%置信区间 1.19，2.59）。我们还研究了 10 个一碳代谢基因中的 22 个多态性与 LINE-1 甲基化水平和乳腺癌之间的关系。我们在这些基因中发现了三个与 LINE-1 甲基化相关的单核苷酸多态性：SLC19A1（rs1051266）；MTRR（rs10380）和 MTHFR（rs1537514），其中一个与乳腺癌风险相关：MTHFR（rs1537514）。PON1（rs757158）与乳腺癌相关，但与甲基化无关。
