(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

• 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
• 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

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）：杂合性的表观遗传丧失（ELOH）是正常人和小鼠发育的常见过程，超出了X染色体失活的众所周知的例子。最近的工作表明，ELOH比以前所欣赏的要普遍得多：超过10％的人和小鼠的常染色体基因受到类似于X灭活的方式受到单相的沉默。由于ELOH，在同一个人中的同一类型的细胞也可能具有截然不同的命运。当影响抑制肿瘤的基因时，具有“良好”等位基因表观遗传沉默的细胞会导致肿瘤，而相反的等位基因选择的细胞仍然正常。 实际上，ELOH会影响许多与癌症相关的常染色体基因。受影响的基因的单相关沉默在有丝分裂上稳定，并导致组织中的马赛克形成，每个斑块中的细胞共享A 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诱发了肿瘤的启动。在这种情况下，可以通过在克隆细胞斑块中共享进攻性ELOH模式来解释癌症现场效应，而相邻斑块中的细胞会耐肿瘤，因为它们携带了无害的模式。 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分析中的独特专业知识。我们将通过结合我们对ELOH的表观基因组学的开创性方法和在乳腺肿瘤发育的小鼠模型中的专业知识来系统地探索并表征表观遗传LOH在癌症场效应中的作用。使用RNA和染色质的深层测序，我们将在多灶性乳腺肿瘤中绘制基因组宽的ELOH模式，并将其与纯化的正常管道上皮细胞中的这种模式进行比较。 如果成功，建议的工作将建立一个新的概念框架，以理解在正常发育和分化过程中形成的克隆谱系的背景下的癌症现场效应。我们还将创建一个强大的实验平台，用于系统研究表观遗传LOH的广泛现象。我们认为，这将对我们对癌症现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，因此我们的发现应提示使用表观遗传修饰剂进行癌症治疗和预防的新策略。