Divison of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, USA.
International Agency for Research on Cancer (IARC), Lyon, France.
Breast Cancer Res. 2019 May 17;21(1):62. doi: 10.1186/s13058-019-1145-9.
Environmental and genetic factors play an important role in the etiology of breast cancer. Several small blood-based DNA methylation studies have reported risk associations with methylation at individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1663 incident cases and 1885 controls, the largest study of blood DNA methylation and breast cancer risk to date.
We assessed associations with methylation at 365,145 CpGs present in the HumanMethylation450 (HM450K) Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts estimated odds ratios (ORs) and 95% confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. Stratified analyses were conducted by age at diagnosis (< 50, ≥ 50), estrogen receptor (ER) status (+/-), and time since blood collection (< 5, 5-10, > 10 years). The false discovery rate (q value) was used to account for multiple testing.
The average age at blood draw ranged from 52.2 to 62.2 years across the four cohorts. Median follow-up time ranged from 6.6 to 8.4 years. The methylation measured at individual CpGs was not associated with breast cancer risk (q value > 0.59). In addition, higher average methylation level was not associated with risk of breast cancer (OR = 0.94, 95% CI = 0.85, 1.05; P = 0.26; P for study heterogeneity = 0.86). We found no evidence of modification of this association by age at diagnosis (P = 0.17), ER status (P = 0.88), time since blood collection (P = 0.98), or CpG location (P = 0.98).
Our data indicate that DNA methylation measured in the blood prior to breast cancer diagnosis in predominantly postmenopausal women is unlikely to be associated with substantial breast cancer risk on the HM450K array. Larger studies or with greater methylation coverage are needed to determine if associations exist between blood DNA methylation and breast cancer risk.
环境和遗传因素在乳腺癌的病因学中起着重要作用。几项基于小体积血液的 DNA 甲基化研究报告了与单个 CpG 及平均甲基化水平的甲基化风险相关性；然而，这些发现需要在更大的前瞻性队列研究中验证。为了研究血液 DNA 甲基化对乳腺癌风险的作用，我们对四项前瞻性队列研究进行了荟萃分析，包括总共 1663 例发病病例和 1885 例对照，这是迄今为止对血液 DNA 甲基化和乳腺癌风险的最大研究。
我们评估了在人类甲基化 450（HM450K）Beadchip 上存在的 365145 个 CpG 的关联，排除了所有研究中质量控制不通过的 CpG。四个队列中的每一个都估计了每个 CpG 与乳腺癌风险之间的比值比（OR）和 95%置信区间（CI）。此外，每个研究都评估了平均甲基化指标与乳腺癌风险之间的关联，调整和未调整细胞类型组成。使用固定效应荟萃分析和逆方差权重对研究特异性 OR 进行合并。通过诊断时的年龄（<50、≥50）、雌激素受体（ER）状态（+/-）和采血后时间（<5、5-10、>10 年）进行分层分析。错误发现率（q 值）用于考虑多次检验。
四项队列的平均采血年龄为 52.2 至 62.2 岁。中位随访时间为 6.6 至 8.4 年。个体 CpG 的甲基化与乳腺癌风险无关（q 值>0.59）。此外，较高的平均甲基化水平与乳腺癌风险无关（OR=0.94，95%CI=0.85，1.05；P=0.26；P 用于研究异质性=0.86）。我们没有发现该关联与诊断时的年龄（P=0.17）、ER 状态（P=0.88）、采血后时间（P=0.98）或 CpG 位置（P=0.98）有修饰作用的证据。
我们的数据表明，在主要为绝经后妇女的乳腺癌诊断前测量的血液中的 DNA 甲基化与 HM450K 阵列上的乳腺癌风险不太可能存在显著相关性。需要更大的研究或更大的甲基化覆盖范围来确定血液 DNA 甲基化与乳腺癌风险之间是否存在关联。
