Centre Jean Perrin, Département d'Oncogénétique, CBRV, 28 place Henri-Dunant, Clermont-Ferrand, France.
Cancer Epidemiol. 2012 Jun;36(3):e177-82. doi: 10.1016/j.canep.2012.02.001. Epub 2012 Mar 7.
Epigenetics, particularly DNA methylation, has recently been shown to be important in breast cancer initiation. We investigated the clinical and prognostic importance of whole blood breast cancer early onset gene 1 (BRCA1) DNA methylation in sporadic breast cancer.
Genomic DNA was extracted from the peripheral blood cells (PBCs) of 902 breast cancer patients at diagnosis, with no BRCA1 mutation, and 990 control women. DNA methylation was measured by quantitative analysis of methylated alleles (QAMA) to estimate the extent of methylation of 2 CpG sites in the promoter region of BRCA1 oncosuppressor.
BRCA1 promoter methylation rate in PBCs was 47.1% with a 95% confidence interval [46.1; 48.1] in breast cancer patients, and 45.9% with a 95% confidence interval [45.0; 46.8] in controls. We found a trend toward BRCA1 promoter hypermethylation in PBCs of sporadic breast cancer patients compared with controls. Association between methylation and clinicopathological features was evaluated using statistical tests. BRCA1 promoter methylation in PBCs increased significantly in breast cancer patients compared with controls, for age over 70 years (p=0.022), in post-menopausal status (p=0.013), for a body mass index (BMI) <20 (p=0.0095) or a waist-to-hip ratio (WHR) ≤76.8 (p=0.0027). We also found an association of increased BRCA1 promoter methylation in PBCs with ACA/ACA genotype for the SNP Thr594Thr in ESR (estrogen receptor gene), known to be associated with breast cancer risk (p=0.092), reflecting the reduced presence of this genotype in this breast cancer case-control study.
Analysis of site-specific DNA methylation in PBCs by QAMA provides quantitative DNA methylation values that may serve as important prognostic indicators.
表观遗传学，特别是 DNA 甲基化，最近被证明在乳腺癌的发生中很重要。我们研究了散发性乳腺癌中全血乳腺癌早期发生基因 1（BRCA1）DNA 甲基化的临床和预后意义。
从 902 名无 BRCA1 突变的诊断为乳腺癌的患者外周血细胞（PBC）和 990 名对照女性中提取基因组 DNA。通过定量分析甲基化等位基因（QAMA）来测量 DNA 甲基化程度，以估计 BRCA1 肿瘤抑制基因启动子区域的 2 个 CpG 位点的甲基化程度。
乳腺癌患者 PBCs 中的 BRCA1 启动子甲基化率为 47.1%（95%置信区间为 46.1%至 48.1%），对照组为 45.9%（95%置信区间为 45.0%至 46.8%）。我们发现，与对照组相比，散发性乳腺癌患者 PBCs 中的 BRCA1 启动子呈过度甲基化趋势。使用统计检验评估甲基化与临床病理特征之间的关系。与对照组相比，BRCA1 启动子在 PBCs 中的甲基化在年龄大于 70 岁的乳腺癌患者中显著增加（p=0.022），在绝经后状态下增加（p=0.013），在 BMI<20 或腰臀比（WHR）≤76.8 时增加（p=0.0095 和 p=0.0027）。我们还发现，与 ESR（雌激素受体基因）中的 SNP Thr594Thr 的 ACA/ACA 基因型相关的 BRCA1 启动子甲基化增加与乳腺癌风险相关（p=0.092），这反映了在该乳腺癌病例对照研究中这种基因型的存在减少。
通过 QAMA 对 PBCs 中的特定部位 DNA 甲基化进行分析，可提供定量的 DNA 甲基化值，这些值可能作为重要的预后指标。
