DNA methylation in benign breast epithelium in relation to age and breast cancer risk
DNA methylation in benign breast epithelium in relation to age and breast cancer risk
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DOI：
10.1158/1055-9965.epi-07-2582
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发表时间：
2008-05-01
影响因子：
3.8
通讯作者：
Lewis, Cheryl M.
中科院分区：
文献类型：
--
作者：
Euhus, David M.;Bu, Dawei;Lewis, Cheryl M.
背景：许多已确定的乳腺癌风险因素与生殖激素暴露的时间和持续时间有关，已知生殖激素会促进乳腺上皮细胞增殖。表观遗传分子钟假说表明，CpG岛甲基化记录了良性上皮细胞的分裂历史。在增殖性上皮组织（如乳腺）中，这可能提供一种基于个体细胞的癌症风险衡量方法。
方法：通过定量多重甲基化特异性聚合酶链反应，对164名女性通过触诊引导下细针穿刺活检获得的290份乳腺良性和恶性上皮细胞样本中的细胞周期蛋白D2、腺瘤性结肠息肉病基因（APC）、HIN1、RASSF1A和视黄酸受体β2的甲基化情况进行检测。采用单变量、多变量和无监督聚类分析来确定肿瘤抑制基因（TSG）甲基化与乳腺癌个人病史、预测的乳腺癌风险以及特定乳腺癌风险因素之间的关系。
结果：RASSF1A甲基化与乳腺癌风险[比值比（OR），5.28；95%置信区间（95%CI），1.95 - 14.32；P = 0.001]、非典型细胞学特征（OR，4.11；95%CI，1.30 - 12.98；P = 0.016）以及需要活检的乳腺良性疾病（OR，6.12；95%CI，1.41 - 26.51；P = 0.016）高度相关。RASSF1A甲基化在32岁至55岁之间呈线性增加。生育次数增加与APC甲基化降低有关。
结论：乳腺良性上皮组织中的肿瘤抑制基因甲基化随年龄增长而增加。由于它与乳腺良性或恶性疾病的个人病史以及预测的乳腺癌风险独立相关，因此它可能对乳腺癌风险分层有价值，并可作为预防试验中的替代终点标志物。
Background: Many established breast cancer risk factors are related to the timing and duration of exposure to reproductive hormones, which are known to drive breast epithelial cell proliferation. The epigenetic molecular clock hypothesis suggests that CpG island methylation records the cell division history of benign epithelium. In proliferative epithelium, such as breast, this may provide an individualized cell-based measure of cancer risk.Methods: Methylation of cyclin D2, APC, HIN1, RASSF1A, and RAR-beta 2 was measured by quantitative multiplex methylation-specific PCR in 290 benign and malignant breast epithelial cell samples obtained by palpation-directed fine-needle aspiration biopsy from 164 women. Univariate, multivariate, and unsupervised cluster analysis was used to establish the relationship between TSG methylation and a personal history of breast cancer, predicted breast cancer risk, and specific breast cancer risk factors.Results: RASSF1A methylation was highly correlated with breast cancer risk [odds ratio (OR), 5.28; 95% confidence interval (95% CI), 1.95-14.32; P = 0.001], atypical cytology (OR, 4.11; 95% CI, 1.30-12.98; P = 0.016), and benign breast disease requiring biopsy (OR, 6.12; 95% CI, 1.41-26.51; P = 0.016). RASSF1A methylation increased linearly between ages 32 and 55. Increasing parity was associated with decreased APC methylation.Conclusions: TSG methylation increases in benign breast epithelium with increasing age. Because it is independently related to a personal history of benign or malignant breast disease and to predicted breast cancer risk, it may have value for breast cancer risk stratification and as a surrogate endpoint marker in prevention trials.