诊断前阿司匹林使用、DNA 甲基化与乳腺癌患者的死亡率：一项基于人群的研究。
Prediagnosis aspirin use, DNA methylation, and mortality after breast cancer: A population-based study.
机构信息
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina.
Department of Epidemiology, Emory University, Atlanta, Georgia.
出版信息
Cancer. 2019 Nov 1;125(21):3836-3844. doi: 10.1002/cncr.32364. Epub 2019 Aug 12.
BACKGROUND
The authors hypothesized that epigenetic changes may help to clarify the underlying biologic mechanism linking aspirin use to breast cancer prognosis. To the authors' knowledge, this is the first epidemiologic study to examine whether global methylation and/or tumor promoter methylation of breast cancer-related genes interact with aspirin use to impact mortality after breast cancer.
METHODS
Prediagnosis aspirin use was assessed through in-person interviews within a population-based cohort of 1508 women diagnosed with a first primary breast cancer in 1996 and 1997. Global methylation in peripheral blood was assessed by long interspersed elements-1 (LINE-1) and the luminometric methylation assay. Promoter methylation of 13 breast cancer-related genes was measured in tumor by methylation-specific polymerase chain reaction and the MethyLight assay. Vital status was determined by the National Death Index through December 31, 2014 (N = 202/476 breast cancer-specific/all-cause deaths identified among 1266 women with any methylation assessment and complete aspirin data). Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs, and the likelihood ratio test was used to evaluate multiplicative interactions.
RESULTS
All-cause mortality was elevated among aspirin users who had methylated promotor of BRCA1 (HR, 1.67; 95% CI, 1.26-2.22), but not among those with unmethylated promoter of BRCA1 (HR, 0.99; 95% CI, 0.67-1.45; P for interaction ≤.05). Decreased breast cancer-specific mortality was observed among aspirin users who had unmethylated promotor of BRCA1 and PR and global hypermethylation of LINE-1 (HR, 0.60, 0.78, and 0.63, respectively; P for interaction ≤.05), although the 95% CIs included the null.
CONCLUSIONS
The current study suggests that the LINE-1 global methylation and promoter methylation of BRCA1 and PR in tumor may interact with aspirin use to influence mortality after breast cancer.
背景
作者假设表观遗传变化可能有助于阐明将阿司匹林使用与乳腺癌预后联系起来的潜在生物学机制。据作者所知，这是第一项研究阿司匹林使用与乳腺癌相关基因的肿瘤启动子甲基化之间相互作用，以影响乳腺癌后死亡率的流行病学研究。
方法
通过对 1996 年和 1997 年诊断为首次原发性乳腺癌的 1508 名女性进行的基于人群的队列中的面对面访谈，评估了发病前的阿司匹林使用情况。通过长散布元件-1（LINE-1）和发光甲基化测定法评估外周血中的整体甲基化。通过甲基化特异性聚合酶链反应和 MethyLight 测定法测量肿瘤中 13 个乳腺癌相关基因的启动子甲基化。通过国家死亡指数确定生存状态，截至 2014 年 12 月 31 日（在 1266 名接受任何甲基化评估和完整阿司匹林数据的女性中，有 202/476 例乳腺癌特异性/所有原因死亡确定）。使用 Cox 比例风险回归估计危险比（HR）和 95%CI，并使用似然比检验评估乘法交互作用。
结果
BRCA1 启动子甲基化的阿司匹林使用者的全因死亡率升高（HR，1.67；95%CI，1.26-2.22），但 BRCA1 启动子未甲基化的阿司匹林使用者的全因死亡率没有升高（HR，0.99；95%CI，0.67-1.45；P 交互作用≤0.05）。BRCA1 和 PR 启动子未甲基化且 LINE-1 整体甲基化升高的阿司匹林使用者的乳腺癌特异性死亡率降低（HR，分别为 0.60、0.78 和 0.63；P 交互作用≤0.05），尽管 95%CI 包含零值。
结论
本研究表明，肿瘤中 LINE-1 整体甲基化和 BRCA1 和 PR 启动子甲基化可能与阿司匹林使用相互作用，影响乳腺癌后的死亡率。
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