Severi Gianluca, Southey Melissa C, English Dallas R, Jung Chol-hee, Lonie Andrew, McLean Catriona, Tsimiklis Helen, Hopper John L, Giles Graham G, Baglietto Laura
Cancer Epidemiology Centre, Cancer Council of Victoria, 615 St Kilda Road, Melbourne, VIC, 3004, Australia.
Breast Cancer Res Treat. 2014 Dec;148(3):665-73. doi: 10.1007/s10549-014-3209-y. Epub 2014 Nov 19.
Aberrant DNA methylation is a key feature of breast carcinoma. We aimed to test the association between breast cancer risk and epigenome-wide methylation in DNA from peripheral blood. Nested case-control study within the prospective Melbourne Collaborative Cohort Study. DNA was extracted from before-diagnosis blood samples (420 incident cases and matched controls). Methylation was measured with the Illumina Infinium Human Methylation 450 BeadChip array. Odds ratio (OR) for epigenome-wide methylation, quantified as the mean beta values across the CpGs, in relation to breast cancer risk were estimated using conditional logistic regression. Overall, the OR for breast cancer was 0.42 (95% CI 0.20-0.90) for the top versus bottom quartile of epigenome-wide DNA methylation and the OR for a one standard deviation increment was 0.69 (95% CI 0.50-0.95; test for linear trend, p = 0.02). Epigenome-wide DNA methylation of CpGs within functional promoters was associated with an increased risk, whereas epigenome-wide DNA methylation of genomic regions outside promoters was associated with decreased risk (test for heterogeneity, p = 0.0002). The increased risk associated with epigenome-wide DNA methylation in functional promoters did not vary by time between blood collection and diagnosis, whereas the inverse association with epigenome-wide DNA methylation outside functional promoters was strongest when the interval from blood collection to diagnosis was less than 5 years and weakest for the longest interval. Epigenome-wide methylation in DNA extracted from peripheral blood collected before diagnosis may have potential utility as markers of breast cancer risk and for early detection.
异常的DNA甲基化是乳腺癌的一个关键特征。我们旨在测试外周血DNA中全基因组甲基化与乳腺癌风险之间的关联。在前瞻性墨尔本协作队列研究中进行巢式病例对照研究。从诊断前的血样中提取DNA（420例新发病例及匹配对照）。使用Illumina Infinium Human Methylation 450 BeadChip芯片阵列测量甲基化。通过条件逻辑回归估计全基因组甲基化的优势比（OR），以CpG位点的平均β值量化，与乳腺癌风险相关。总体而言，全基因组DNA甲基化最高四分位数与最低四分位数相比，乳腺癌的OR为0.42（95%可信区间0.20 - 0.90），一个标准差增加的OR为0.69（95%可信区间0.50 - 0.95；线性趋势检验，p = 0.02）。功能启动子内CpG位点的全基因组DNA甲基化与风险增加相关，而启动子外基因组区域的全基因组DNA甲基化与风险降低相关（异质性检验，p = 0.0002）。功能启动子内全基因组DNA甲基化相关的风险增加在采血与诊断之间的时间上没有差异，而与功能启动子外全基因组DNA甲基化的负相关在采血到诊断的间隔小于5年时最强，间隔最长时最弱。诊断前采集的外周血DNA中的全基因组甲基化可能具有作为乳腺癌风险标志物和早期检测的潜在用途。
