CpG Island Methylator Phenotypes in Breast Cancer

描述(申请人提供)：CpG岛甲基化表型(CIMP)是在癌症中观察到的一种独特的表观遗传现象。具有CIMP的肿瘤通常表现为多个启动子CpG岛的同时高甲基化。CIMP的病因尚不清楚。一个非常重要的问题是，CIMPS是否是癌细胞信号转导系统放松调控的结果。具体地说，我们的初步研究表明，ERA信号的中断在一定程度上促进了乳腺癌CIMPS的发展。我们假设这种干扰会导致ERA反应靶标的转录谱改变，其中一些通过表观遗传机制下调。这些反应靶标的同时高甲基化是这种转录沉默的标志(或分子遗迹)，并创建了特定的模式，在表观遗传学上被描述为CIMPS。在这项修订的应用中，全球和基因特异性甲基化分析将在原发肿瘤、邻近正常组织和无关的正常乳房整形手术样本中进行。一种新的计算算法，称为遗传聚类，将被用于生成一个系统发育模型，该模型模拟从癌前病变到增生、导管原位癌到浸润性癌的甲基化改变的历史。由遗传聚类法生成的不同CIMPS谱可以代表乳腺癌发展的不同阶段。将特别注意寻找与Era相关的CIMP，这些CIMP可以预测患者对内分泌治疗的内在抵抗。遗传和生化研究将巩固ERA共同调节因子在内分泌耐药机制中的重要作用。由于与其他信号通路的串扰，ERA共调节因子可能在乳腺癌细胞中异常表达。这可能导致ERA反应靶点的子集的表观遗传沉默，这将通过定量分析和“易耐药”原发肿瘤的亚硫酸氢盐测序来验证。本研究对激素受体阳性肿瘤的临床治疗具有一定的指导意义。今天，预测患者内分泌治疗结果的分子信息的匮乏带来了识别新类型生物标记物的紧迫性。在这一点上，与ERA信号相关的启动子高甲基化是一个尚未开发的抗药性疾病预测因子资源。这种类型的表观遗传学研究将有助于识别耐药的CIMPS患者，以便在未来进行替代治疗。

DESCRIPTION (provided by applicant): CpG island methylator phenotype (CIMP) is a unique epigenetic phenomenon observed in cancer. Tumors possessing a CIMP usually display concurrent hypermethylation of multiple promoter CpG islands. The causes of CIMP are unknown. An issue of great importance is whether CIMPs are the result of a systematic deregulation of signal transduction in cancer cells. Specifically, our preliminary studies suggest that ERa signaling disruption contributes, in part, to the development of CIMPs in breast cancer. We hypothesize that this disturbance results in altered transcription profiles of ERa-responsive targets, some of which are down- regulated via epigenetic mechanisms. Concurrent hypermethylation of these responsive targets is a hallmark (or molecular relic) of this transcriptional silencing and creates specific patterns, which are epigenetically depicted as CIMPs. In this revised application, global and gene-specific methylation analysis will be conducted in primary tumors, adjacent normals, and unrelated normal mammoplasty samples. A novel computational algorithm, called Heritable Clustering, will be used to generate a phylogenetic model that simulates the history of methylation alteration from pre-neoplastic lesions to hyperplasia to ductal carcinoma in situ to invasive cancers. Different CIMPs profiles generated by Heritable Clustering can represent different stages of breast cancer development. Specific attention will be made to find ERa-related CIMPs that predict patients' intrinsic resistance to endocrine treatment. Genetic and biochemical studies will solidify an important role of ERa co-regulators in contributing to the mechanisms of endocrine resistance. As a result of crosstalk with other signaling pathways, ERa co-regulators can be abnormally expressed in breast cancer cells. This may result in epigenetic silencing of a subset of ERa-responsive targets, which will be validated by quantitative assays and bisulfite sequencing in "resistance-prone" primary tumors. The present study has a practical ramification for clinical management of hormone receptor-positive tumors. Today, the paucity of molecular information to predict the outcome of endocrine treatment in patients brings urgency for identifying new types of biomarkers. In this regard, promoter hypermethylation related to ERa signaling is an untapped resource of predictors for the resistance disease. This type of epigenetic studies will be useful for identifying patients with resistant-CIMPs for alternative therapies in the future.