CpG Island Methylator Phenotypes in Breast Cancer

描述（由申请人提供）：CpG岛甲基化表型（CIMP）是在癌症中观察到的独特表观遗传现象。具有CIMP的肿瘤通常显示多个启动子CpG岛的同时高甲基化。CIMP的原因尚不清楚。一个非常重要的问题是CIMPs是否是癌细胞中信号转导系统失调的结果。具体地说，我们的初步研究表明，ER α信号中断有助于，部分，在乳腺癌中的CIMPs的发展。我们假设这种干扰导致ER α应答靶点的转录谱改变，其中一些通过表观遗传机制下调。这些反应性靶点的同时高甲基化是这种转录沉默的标志（或分子遗迹），并产生特定的模式，表观遗传学上被描述为CIMPs。在这一修订后的申请中，将在原发性肿瘤、相邻正常人和无关的正常乳房成形术样本中进行全局和基因特异性甲基化分析。一种新的计算算法，称为遗传聚类，将被用来生成一个系统发育模型，模拟从癌前病变的甲基化改变的历史增生导管原位癌浸润性癌症。遗传聚类产生的不同CIMPs谱可以代表乳腺癌发展的不同阶段。将特别注意寻找预测患者对内分泌治疗的内在抗性的ER α相关CIMPs。遗传和生物化学研究将巩固ER α共调节因子在促进内分泌抗性机制中的重要作用。由于与其他信号传导途径的串扰，ER α共调节因子可以在乳腺癌细胞中异常表达。这可能导致ER α响应性靶标的亚组的表观遗传沉默，这将通过“耐药倾向”原发性肿瘤中的定量测定和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实际意义。今天，缺乏分子信息来预测患者内分泌治疗的结果，迫切需要识别新类型的生物标志物。在这方面，与ER α信号传导相关的启动子超甲基化是抗性疾病的预测因子的未开发资源。这种类型的表观遗传学研究将有助于确定患者与耐药CIMPs的替代疗法在未来。

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.