Tang Haibo, Yang Desong, Han Chaofei, Mu Ping
Department of Metabolic and Bariatric Surgery, The Third Xiangya Hospital, Central South University, Changsha, China.
Department of Thoracic Surgery II, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Front Oncol. 2021 Sep 28;11:745918. doi: 10.3389/fonc.2021.745918. eCollection 2021.
Smoking was strongly associated with breast cancer in previous studies. Whether smoking promotes breast cancer through DNA methylation remains unknown.
Two-sample Mendelian randomization (MR) analyses were conducted to assess the causal effect of smoking-related DNA methylation on breast cancer risk. We used 436 smoking-related CpG sites extracted from 846 middle-aged women in the ARIES project as exposure data. We collected summary data of breast cancer from one of the largest meta-analyses, including 69,501 cases for ER+ breast cancer and 21,468 cases for ER- breast cancer. A total of 485 single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) for smoking-related DNA methylation. We further performed an MR Steiger test to estimate the likely direction of causal estimate between DNA methylation and breast cancer. We also conducted colocalization analysis to evaluate whether smoking-related CpG sites shared a common genetic causal SNP with breast cancer in a given region.
We established four significant associations after multiple testing correction: the CpG sites of cg2583948 [OR = 0.94, 95% CI (0.91-0.97)], cg0760265 [OR = 1.07, 95% CI (1.03-1.11)], cg0420946 [OR = 0.95, 95% CI (0.93-0.98)], and cg2037583 [OR =1.09, 95% CI (1.04-1.15)] were associated with the risk of ER+ breast cancer. All the four smoking-related CpG sites had a larger variance than that in ER+ breast cancer (all < 1.83 × 10) in the MR Steiger test. Further colocalization analysis showed that there was strong evidence (based on PPH4 > 0.8) supporting a common genetic causal SNP between the CpG site of cg2583948 [with expression (PPH4 = 0.958)] and ER+ breast cancer. There were no causal associations between smoking-related DNA methylation and ER- breast cancer.
These findings highlight potential targets for the prevention of ER+ breast cancer. Tissue-specific epigenetic data are required to confirm these results.
在以往的研究中，吸烟与乳腺癌密切相关。吸烟是否通过DNA甲基化促进乳腺癌的发生仍不清楚。
进行两样本孟德尔随机化（MR）分析，以评估吸烟相关DNA甲基化对乳腺癌风险的因果效应。我们使用从ARIES项目的846名中年女性中提取的436个与吸烟相关的CpG位点作为暴露数据。我们从一项最大的荟萃分析中收集了乳腺癌的汇总数据，其中包括69501例雌激素受体阳性（ER+）乳腺癌病例和21468例雌激素受体阴性（ER-）乳腺癌病例。总共选择了485个单核苷酸多态性（SNP）作为与吸烟相关DNA甲基化的工具变量（IV）。我们进一步进行了MR Steiger检验，以估计DNA甲基化与乳腺癌之间因果估计的可能方向。我们还进行了共定位分析，以评估与吸烟相关的CpG位点在给定区域是否与乳腺癌共享一个共同的遗传因果SNP。
经过多重检验校正后，我们建立了四个显著关联：cg2583948的CpG位点[比值比（OR）=0.94，95%置信区间（CI）（0.91 - 0.97）]、cg0760265[OR = 1.07，95% CI（1.03 - 1.11）]、cg0420946[OR = 0.95，95% CI（0.93 - 0.98）]和cg2037583[OR = 1.09，95% CI（1.04 - 1.15）]与ER+乳腺癌风险相关。在MR Steiger检验中，所有四个与吸烟相关的CpG位点的方差均大于ER+乳腺癌中的方差（均<1.83×10）。进一步的共定位分析表明，有强有力的证据（基于后验概率PPH4>0.8）支持cg2583948的CpG位点[表达（PPH4 = 0.958）]与ER+乳腺癌之间存在共同的遗传因果SNP。吸烟相关DNA甲基化与ER-乳腺癌之间没有因果关联。
这些发现突出了预防ER+乳腺癌的潜在靶点。需要组织特异性表观遗传数据来证实这些结果。
