Genome-wide methylation analysis identifies genes specific to breast cancer hormone receptor status and risk of recurrence.
Genome-wide methylation analysis identifies genes specific to breast cancer hormone receptor status and risk of recurrence.
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DOI：
10.1158/0008-5472.can-11-1630
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发表时间：
2011-10-01
期刊：
影响因子：
11.2
通讯作者：
Sukumar S
中科院分区：
文献类型：
--
作者：
Fackler MJ;Umbricht CB;Williams D;Argani P;Cruz LA;Merino VF;Teo WW;Zhang Z;Huang P;Visvananthan K;Marks J;Ethier S;Gray JW;Wolff AC;Cope LM;Sukumar S
为了更好地了解激素受体阳性和阴性乳腺癌的生物学特征，并确定疾病进展的甲基化基因标记物，我们使用Illumina Infinium HumanMethation27阵列对103例原发性浸润性乳腺癌和21例正常乳腺样本进行了全基因组甲基化阵列分析，共查询了27,578个CpG基因座。雌激素和/或孕激素受体阳性的肿瘤比ER阴性的肿瘤显示更多的甲基化基因。然而，与ER阳性肿瘤相比，ER阴性肿瘤中的高甲基化位点聚集在离转录起点更近的位置。CpG基因座的ER分类器集被识别出来，它独立地将原发肿瘤划分为ER亚型。40个(32个新发现，8个已知)CpG基因座显示ER阳性或ER阴性肿瘤的差异甲基化。使用来自癌症基因组图谱(TCGA)的独立的、公开可用的甲基组数据集，在电子计算机中验证了40个ER亚型特定的基因座。此外，我们确定了100个与疾病进展显著相关的甲基化CpG基因座；这些基因座中的大多数都是信息性的，特别是在ER阴性的乳腺癌中。总体而言，这组基因在含有同源异型盒的基因中高度丰富。这项初步研究证明了乳腺癌甲基组的稳健性，并说明了它在分层和揭示乳腺癌ER亚型之间的生物学差异方面的潜力。此外，它定义了候选ER特异性标记物，并确定了预测ER亚组内结果的潜在标记物。
To better understand the biology of hormone receptor-positive and negative breast cancer and to identify methylated gene markers of disease progression, we performed a genome-wide methylation array analysis on 103 primary invasive breast cancers and 21 normal breast samples using the Illumina Infinium HumanMethylation27 array that queried 27,578 CpG loci. Estrogen and/or progesterone receptor-positive tumors displayed more hypermethylated loci than ER-negative tumors. However, the hypermethylated loci in ER-negative tumors were clustered closer to the transcriptional start site compared to ER-positive tumors. An ER-classifier set of CpG loci was identified, which independently partitioned primary tumors into ER-subtypes. Forty (32 novel, 8 previously known) CpG loci showed differential methylation specific to either ER-positive or ER-negative tumors. Each of the 40 ER-subtype-specific loci was validated in silico using an independent, publicly available methylome dataset from The Cancer Genome Atlas (TCGA). In addition, we identified 100 methylated CpG loci that were significantly associated with disease progression; the majority of these loci were informative particularly in ER-negative breast cancer. Overall, the set was highly enriched in homeobox containing genes. This pilot study demonstrates the robustness of the breast cancer methylome and illustrates its potential to stratify and reveal biological differences between ER-subtypes of breast cancer. Further, it defines candidate ER-specific markers and identifies potential markers predictive of outcome within ER subgroups.