(PQD4) Epigenetic loss of heterozygosity as a driver of the cancer field effect

(PQD4) 表观遗传杂合性丧失是癌症场效应的驱动因素

基本信息

批准号：
8686513
负责人：
Alexander Gimelbrant
金额：
$ 22.2万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-17 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8686513
关键词：
Affect Age Alleles Biological Breast Cancer Model Cell Nucleus Cells Characteristics Chromatin Complex DNA Development Duct (organ) structure Embryo Epigenetic Process Epithelial Cells Female Gene Expression Profile Genes Genetic Genetic Polymorphism Goals Human Human Development Individual Laboratories Lead Loss of Heterozygosity Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Mammary gland Maps Measures Mouse Mammary Tumor Virus Mus Normal Cell Pattern Population Premalignant Process RNA Resistance Role Sample Size Sampling Stem cells Testing Tissues Transgenic Mice Tumor Suppressor Genes Work X Inactivation cancer cell cancer prevention cancer therapy deep sequencing density epigenomics genome-wide malignant breast neoplasm mouse development mouse model neoplastic cell public health relevance research study transcriptome sequencing tumor tumor initiation tumor progression

项目摘要

DESCRIPTION (provided by applicant): Epigenetic loss of heterozygosity (eLOH) is a common process in normal human and mouse development, above and beyond the well-known example of X chromosome inactivation. Recent work has shown that eLOH is much more common than previously appreciated: over 10% of autosomal genes in human and mouse are subject to monoallelic silencing in a way that resembles X-inactivation. As a result of eLOH, even cells of the same type in the same individual can have dramatically different fates. When a tumor suppressing gene is affected, cells with the epigenetic silencing of the "good" allele give rise to tumors, while the cells with the opposite allelic choice remain normal. In fact, eLOH affects many cancer-related autosomal genes. Monoallelic silencing of the affected genes is mitotically stable and leads to formation of a mosaic in tissue, with cells in each patch sharing a particular genome-wide eLOH pattern. We hypothesize that some eLOH patterns predispose cells to tumor initiation by causing functional LOH in critical genes. The cancer field effect woul be explained in this case by sharing the offensive eLOH pattern within clonal cell patches, while cells in neighboring patches would be tumor resistant because they carried harmless patterns. This project combines the unique expertise of two leading laboratories in breast cancer modeling and in genome-wide eLOH analysis. We will systematically explore and characterize the role of epigenetic LOH in the cancer field effect by combining our pioneering approaches to epigenomics of eLOH and expertise in mouse models of mammary tumor development. Using deep sequencing of RNA and chromatin, we will map genome- wide eLOH patterns in multifocal mammary tumors and compare them to such patterns in purified normal duct epithelial cells. If successful, the proposed work will establish a new conceptual framework for understanding the cancer field effect in the context of clonal lineages formed during normal development and differentiation. We will also have created a robust experimental platform for systematic study of the widespread phenomenon of epigenetic LOH. We believe this will have a major impact on our understanding of the epigenetic mechanisms underlying the cancer field effect. Since epigenetic processes are in principle reversible, our findings should suggest new strategies in cancer treatment and prevention using epigenetic modifiers.

描述（由申请人提供）：表观遗传杂合性丢失（eLOH）是正常人类和小鼠发育中的常见过程，超出了众所周知的 X 染色体失活的例子。最近的研究表明，eLOH 比之前认识的更为常见：人类和小鼠中超过 10% 的常染色体基因以类似于 X 失活的方式遭受单等位基因沉默。由于 eLOH，即使同一个体中相同类型的细胞也可能具有截然不同的命运。当肿瘤抑制基因受到影响时，具有“好”等位基因表观遗传沉默的细胞会产生肿瘤，而具有相反等位基因选择的细胞则保持正常。事实上，eLOH 影响许多与癌症相关的常染色体基因。受影响基因的单等位基因沉默是有丝分裂稳定的，并导致组织中马赛克的形成，每个斑块中的细胞共享一个特定的全基因组 eLOH 模式。我们假设某些 eLOH 模式通过在关键基因中引起功能性 LOH 来使细胞易于发生肿瘤。在这种情况下，癌症场效应可以通过在克隆细胞斑块内共享攻击性 eLOH 模式来解释，而相邻斑块中的细胞将具有肿瘤抗性，因为它们携带无害的模式。该项目结合了两个领先实验室在乳腺癌建模和全基因组 eLOH 分析方面的独特专业知识。我们将通过结合 eLOH 表观基因组学的开创性方法和乳腺肿瘤发展小鼠模型的专业知识，系统地探索和表征表观遗传 LOH 在癌症场效应中的作用。利用 RNA 和染色质的深度测序，我们将绘制多灶性乳腺肿瘤中全基因组 eLOH 模式，并将其与纯化的正常导管上皮细胞中的此类模式进行比较。如果成功，拟议的工作将建立一个新的概念框架，用于理解正常发育和分化过程中形成的克隆谱系背景下的癌症场效应。我们还将创建一个强大的实验平台，用于系统研究普遍存在的表观遗传 LOH 现象。我们相信这将对我们对癌症场效应背后的表观遗传机制的理解产生重大影响。由于表观遗传过程原则上是可逆的，因此我们的研究结果应该提出使用表观遗传修饰剂治疗和预防癌症的新策略。