Blood DNA methylation and breast cancer risk: a meta-analysis of four prospective cohort studies
Blood DNA methylation and breast cancer risk: a meta-analysis of four prospective cohort studies
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DOI：
10.1186/s13058-019-1145-9
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发表时间：
2019-05-17
影响因子：
7.4
通讯作者：
Garcia-Closas, Montserrat
中科院分区：
文献类型：
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作者：
Bodelon, Clara;Ambatipudi, Srikant;Garcia-Closas, Montserrat
背景环境和遗传因素在乳腺癌的病因中起着重要作用。几项基于血液的小型DNA甲基化研究已经报告了个体CPGS和平均甲基化水平的甲基化与风险相关；然而，这些发现需要在更大的前瞻性队列研究中进行验证。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名对照，这是迄今为止关于血液DNA甲基化与乳腺癌风险的最大规模研究。方法在排除了所有研究中未通过质量控制的CPGS后，我们评估了人类甲基化450(HM450K)珠芯片中存在的365,145个CPGS与甲基化的相关性。四个队列中的每一个都估计了个体CpG与乳腺癌风险之间的关联的优势比(OR)和95%的可信区间(CI)。此外，每项研究都评估了平均甲基化措施与乳腺癌风险之间的关联，调整和未调整的细胞类型组成。使用具有逆方差权重的固定效应荟萃分析将特定研究的OR值合并。按确诊时的年龄(0.59)进行分层分析。此外，高甲基化水平与乳腺癌发病风险无关(OR=0.94，95%CI=0.85，1.05；P=0.26；研究异质性P=0.86)。我们没有发现这种关联因确诊时的年龄(P=0.17)、ER状态(P=0.88)、采血时间(P=0.98)或CpG位置(P=0.98)而改变的证据。结论我们的数据表明，绝经后妇女在诊断乳腺癌之前在血液中检测到的DNA甲基化不太可能与HM450K阵列上的乳腺癌风险显著相关。需要更大规模的研究或更大的甲基化覆盖率来确定血液DNA甲基化与乳腺癌风险之间是否存在关联。
BackgroundEnvironmental 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.MethodsWe 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 (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).ConclusionsOur 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.