血液 DNA 甲基化与乳腺癌：姐妹研究中的前瞻性病例对照分析。
Blood DNA Methylation and Breast Cancer: A Prospective Case-Cohort Analysis in the Sister Study.
机构信息
Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC.
Epigenetics & Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC.
出版信息
J Natl Cancer Inst. 2020 Jan 1;112(1):87-94. doi: 10.1093/jnci/djz065.
BACKGROUND
Peripheral blood DNA methylation may be associated with breast cancer, but studies of candidate genes and global and genome-wide DNA methylation have been inconsistent.
METHODS
We performed an epigenome-wide study using Infinium HumanMethylation450 BeadChips with prospectively collected blood DNA samples from the Sister Study (1552 cases, 1224 subcohort). Differentially methylated cytosine-phosphate-guanine sites (dmCpGs) were identified using case-cohort proportional hazard models and replicated using deposited data from European Prospective Investigation into Cancer and Nutrition in Italy (EPIC-Italy) (n = 329). The correlation between methylation and time to diagnosis was examined using robust linear regression. Causal or consequential relationships of methylation to breast cancer were examined by Mendelian randomization using OncoArray 500 K single-nucleotide polymorphism data. All statistical tests were two-sided.
RESULTS
We identified 9601 CpG markers associated with invasive breast cancer (false discovery rate = q < 0.01), with 510 meeting a strict Bonferroni correction threshold (10-7). A total of 2095 of these CpGs replicated in the independent EPIC-Italy dataset, including 144 meeting the Bonferroni threshold. Sister Study women who developed ductal carcinoma in situ had methylation similar to noncases. Most (1501, 71.6%) dmCpGs showed lower methylation in invasive cases. In case-only analysis, methylation was statistically significantly associated (false discovery rate = q < 0.05) with time to diagnosis for 892 (42.6%) of the dmCpGs. Analyses based on genetic association suggest that methylation differences are likely a consequence rather than a cause of breast cancer. Pathway analysis shows enrichment of breast cancer-related gene pathways, and dmCpGs are overrepresented in known breast cancer susceptibility genes.
CONCLUSIONS
Our findings suggest that the DNA methylation profile of blood starts to change in response to invasive breast cancer years before the tumor is clinically detected.
背景
外周血 DNA 甲基化可能与乳腺癌有关，但候选基因、全基因组和全基因组 DNA 甲基化的研究结果并不一致。
方法
我们使用前瞻性收集的来自 Sister 研究（1552 例病例，1224 亚组）的血液 DNA 样本进行了全基因组 DNA 甲基化研究。使用病例-亚组比例风险模型识别差异甲基化胞嘧啶-磷酸-鸟嘌呤位点（dmCpGs），并使用意大利欧洲前瞻性癌症与营养研究（EPIC-Italy）中已存入的数据进行验证（n=329）。使用稳健线性回归检验了甲基化与诊断时间之间的相关性。使用 OncoArray 500 K 单核苷酸多态性数据进行孟德尔随机化检验了甲基化与乳腺癌之间的因果关系。所有统计检验均为双侧检验。
结果
我们鉴定出与浸润性乳腺癌相关的 9601 个 CpG 标记物（错误发现率=q<0.01），其中 510 个符合严格的 Bonferroni 校正阈值（10-7）。这些 CpG 中有 2095 个在独立的 EPIC-Italy 数据集得到验证，其中包括 144 个符合 Bonferroni 阈值的 CpG。发生导管原位癌的 Sister 研究女性的甲基化与非病例相似。大多数（1501 个，71.6%）dmCpGs 在浸润性病例中表现出较低的甲基化。在病例仅分析中，892 个（42.6%）dmCpG 的甲基化与诊断时间之间存在统计学显著关联（错误发现率=q<0.05）。基于遗传关联的分析表明，甲基化差异可能是乳腺癌的结果而不是原因。通路分析显示乳腺癌相关基因通路的富集，并且 dmCpG 在已知的乳腺癌易感基因中过表达。
结论
我们的研究结果表明，血液的 DNA 甲基化图谱在肿瘤临床上检测到之前的多年就开始发生改变，以应对浸润性乳腺癌。
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