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的肿瘤通常同时显示多个启动子CpG岛的高甲基化。CIMP的病因尚不清楚。一个非常重要的问题是，CIMPs是否是肿瘤细胞中信号转导系统失调的结果。具体来说，我们的初步研究表明，ERa信号中断在一定程度上促进了乳腺癌中CIMPs的发展。我们假设这种干扰导致era应答靶标的转录谱改变，其中一些通过表观遗传机制下调。这些反应性靶标的同步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，这些模式在表观遗传学上被描述为CIMPs。在这个修订的应用程序中，将对原发肿瘤、邻近正常和不相关的正常乳房成形术样本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，将用于生成一个系统发育模型，模拟从肿瘤前病变到增生到导管原位癌到浸润性癌症的甲基化改变的历史。遗传聚类产生的不同的CIMPs谱可以代表乳腺癌发展的不同阶段。我们将特别关注era相关的CIMPs，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协同调节因子在内分泌抵抗机制中的重要作用。由于与其他信号通路的串扰，ERa共调节因子可在乳腺癌细胞中异常表达。这可能会导致一部分era应答靶点的表观遗传沉默，这将通过定量分析和亚硫酸盐测序在“耐药易发”的原发性肿瘤中得到验证。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，由于缺乏分子信息来预测患者内分泌治疗的结果，因此迫切需要识别新型生物标志物。在这方面，与ERa信号相关的启动子超甲基化是抗性疾病尚未开发的预测因子。这种类型的表观遗传学研究将有助于识别耐药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.