DNA methylation and hormone receptor status in breast cancer.
DNA methylation and hormone receptor status in breast cancer.
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乳腺癌中的DNA甲基化和激素受体状态。
DOI：
10.1186/s13148-016-0184-7
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发表时间：
2016
影响因子：
5.7
通讯作者：
Rauscher GH
中科院分区：
文献类型：
--
作者：
Benevolenskaya EV;Islam AB;Ahsan H;Kibriya MG;Jasmine F;Wolff B;Al-Alem U;Wiley E;Kajdacsy-Balla A;Macias V;Rauscher GH
我们在芝加哥乳腺癌护理（BCCC）研究中的一组不同种族的患者中，使用癌症基因组图谱（TCGA）的数据，研究肿瘤DNA甲基化的差异是否与更具侵袭性的激素受体阴性乳腺癌相关。从BCCC中招募的75名患者（21名白色，31名非洲裔美国人和23名西班牙裔）（训练数据集）的福尔马林固定的石蜡包埋样本中提取DNA。如果肿瘤雌激素和孕激素（ER/PR）受体均为阴性，则激素受体状态定义为阴性（N = 22/75）。使用Illumina GoldenGate测定法分析807个基因启动子内1505个CpG位点处的DNA甲基化。差异DNA甲基化作为激素受体状态的预测因子进行了测试，同时控制错误发现率，并分配给最接近相应CpG位点的基因。接下来，使用关于DNA甲基化的TCGA数据（验证数据集）验证预测ER/PR状态的那些基因，并检查CpG甲基化和基因表达之间的相关性。在训练数据集中，5.7%的启动子平均甲基化值（46/807）与受体状态相关，P <0.05;其中88%（38/46）的启动子甲基化与受体阳性疾病相关。FZD 9、MME、BCAP 31、HDAC 9、PAX 6、SCGB 3A1、PDGFRA、IGFBP3和PTGS 2基因的超甲基化最强有力地预测受体阳性疾病。来自训练数据集的24个预测基因中的21个在验证数据集中得到确认。在22个基因中，有19个基因的DNA甲基化水平与基因活性相关，这些基因的基因表达数据是可用的。乳腺肿瘤中较高水平的启动子甲基化与激素受体阳性状态密切相关。对于在我们的训练数据集中鉴定为ER/PR受体状态预测因子的大多数基因，DNA甲基化与稳定的基因表达水平相关。当对具有不同种族分布的独立样本集进行评估时，预测因子表现良好，从而提供了这组DNA甲基化生物标志物可能推广到前瞻性患者样本的证据。本文的在线版本（doi：10.1186/s13148 - 016 - 0184 - 7）包含补充材料，可供授权用户使用。
We examined whether differences in tumor DNA methylation were associated with more aggressive hormone receptor-negative breast cancer in an ethnically diverse group of patients in the Breast Cancer Care in Chicago (BCCC) study and using data from The Cancer Genome Atlas (TCGA). DNA was extracted from formalin-fixed, paraffin-embedded samples on 75 patients (21 White, 31 African-American, and 23 Hispanic) (training dataset) enrolled in the BCCC. Hormone receptor status was defined as negative if tumors were negative for both estrogen and progesterone (ER/PR) receptors (N = 22/75). DNA methylation was analyzed at 1505 CpG sites within 807 gene promoters using the Illumina GoldenGate assay. Differential DNA methylation as a predictor of hormone receptor status was tested while controlling for false discovery rate and assigned to the gene closest to the respective CpG site. Next, those genes that predicted ER/PR status were validated using TCGA data with respect to DNA methylation (validation dataset), and correlations between CpG methylation and gene expression were examined. In the training dataset, 5.7 % of promoter mean methylation values (46/807) were associated with receptor status at P < 0.05; for 88 % of these (38/46), hypermethylation was associated with receptor-positive disease. Hypermethylation for FZD9, MME, BCAP31, HDAC9, PAX6, SCGB3A1, PDGFRA, IGFBP3, and PTGS2 genes most strongly predicted receptor-positive disease. Twenty-one of 24 predictor genes from the training dataset were confirmed in the validation dataset. The level of DNA methylation at 19 out 22 genes, for which gene expression data were available, was associated with gene activity. Higher levels of promoter methylation strongly correlate with hormone receptor positive status of breast tumors. For most of the genes identified in our training dataset as ER/PR receptor status predictors, DNA methylation correlated with stable gene expression level. The predictors performed well when evaluated on independent set of samples, with different racioethnic distribution, thus providing evidence that this set of DNA methylation biomarkers will likely generalize to prospective patient samples. The online version of this article (doi:10.1186/s13148-016-0184-7) contains supplementary material, which is available to authorized users.