Genetic Basis of Signaling Heterogeneity in Human Follicular Lymphoma

人滤泡性淋巴瘤信号异质性的遗传基础

基本信息

批准号：
8444348
负责人：
RONALD LEVY
金额：
$ 45.97万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444348
关键词：
Antigens B-Lymphocytes Biology Cell Separation Cells Clinical Clonal Evolution Clonal Expansion Collection Common Neoplasm Complement DNA DNA Resequencing DNA Sequence DNA analysis DNA copy number Data Diagnosis Disease Elements Etiology Follicular Lymphoma Gene Expression Genes Genetic Heavy-Chain Immunoglobulins Heterogeneity Human Individual Indolent Knowledge Lead Malignant - descriptor Malignant Neoplasms Methods Modeling Molecular Profiling Mutation Pathway interactions Patients Pattern Phenotype Phosphoric Monoester Hydrolases Phylogenetic Analysis Plant Roots Population Primary Neoplasm Receptor Signaling Receptors, Antigen, B-Cell Recurrence Sampling Signal Pathway Signal Transduction Signaling Pathway Gene Somatic Mutation Sorting - Cell Movement Specimen T-Lymphocyte Technology Testing Time Trees Variant base chemotherapy comparative genetic analysis genome-wide member neoplastic cell next generation novel primitive cell progenitor prognostic public health relevance response tumor variable region gene

项目摘要

DESCRIPTION (provided by applicant): Follicular lymphoma (FL) is generally an incurable disease. In each case the tumor is composed of a clonal population of B cells with a unique B cell antigen receptor (BCR). We have recently discovered that at the time of diagnosis, each FL tumor contains a subpopulation of tumor cells that has defective signaling through its B cell antigen receptor (1). The size of this BCR insensitive tumor subpopulation expands over time, and it predicts poor response to chemotherapy and a shorter overall survival. Thus, we pose the question "what is the relationship between the two subpopulations of tumor cells in follicular lymphoma- the BCR sensitive and the BCR insensitive?" We postulate several models:1. The BCR insensitive population arises from the BCR sensitive population, 2. Each of the two tumor subpopulations arises from a common but rare tumor-initiating cell, or 3. The BCR insensitive population is the more primitive cell that initially gives rise to the dominant BCR sensitive population but eventually dominates due to negative selective forces of antigenic stimulation or differential sensitivity to therapy. We will distinguish between these hypotheses by separating the two subpopulations of tumor cells from individual cases and by performing comparative genetic analyses on the respective pairs. We will clone and sequence the VDJ region genes from each subpopulation and examine their patterns of V region somatic mutations. By comparing their respective evolutionary paths we will infer the clonal relationships between the BCR sensitive and BCR insensitive subpopulations. In a second approach we will compare the global patterns of DNA gains and losses between the two tumor subpopulations and identify the changes unique to each. All tumor cells should share the driver DNA gains and losses with the progenitor tumor cell; additional gains and losses should reveal how the two subpopulations evolved in relation to each other. Finally, we will search for the root cause of BCR insensitivity in each case. Using next generation DNA sequencing technology, we will conduct large scale deep resequencing of genes of the BCR signaling pathway. We expect to find mutations in the proximal members of the pathway. In order to discover other differences between BCR sensitive and BCR insensitive tumor cell subsets we will compare their gene expression profiles.

描述（由申请人提供）：卵泡淋巴瘤（FL）通常是一种无法治愈的疾病。在每种情况下，肿瘤由具有独特的B细胞抗原受体（BCR）的B细胞的克隆群组成。我们最近发现，在诊断时，每个FL肿瘤都包含通过其B细胞抗原受体有缺陷的信号传导的肿瘤细胞的亚群（1）。这种BCR不敏感的肿瘤亚群的大小会随着时间的推移而扩大，并且预测对化学疗法的反应不佳和整体存活率较短。因此，我们提出了一个问题：“卵泡淋巴瘤中肿瘤细胞的两个亚群 - BCR敏感和BCR不敏感之间有什么关系？”我们假设几种型号：1。 BCR不敏感的人群源于BCR敏感人群，2。肿瘤亚群中的每个人中的每一个均来自一个常见但罕见的肿瘤发射细胞或3个。BCR不敏感的人群是最原始的细胞，最初引起了主导的BCR敏感人群，但最终导致抗原刺激或差异化敏感性的负面选择性占主导地位。我们将通过将肿瘤细胞的两个亚群与单个病例分开，并通过对各对的比较遗传分析来区分这些假设。我们将从每个亚群中克隆并对VDJ区域基因进行测序，并检查其V区域体细胞突变的模式。通过比较它们各自的进化路径，我们将推断BCR敏感和BCR不敏感的亚群之间的克隆关系。在第二种方法中，我们将比较两种肿瘤亚群之间的DNA增益和损失的全局模式，并确定每个肿瘤的独特变化。所有肿瘤细胞应与祖细胞肿瘤细胞共享驱动器DNA的增长和损失。额外的收益和损失应揭示这两个亚群相对于彼此的发展。最后，我们将在每种情况下搜索BCR不敏感的根本原因。使用下一代DNA测序技术，我们将对BCR信号途径的基因进行大规模的深度重新配置。我们希望在途径的近端成员中找到突变。为了发现BCR敏感和BCR不敏感的肿瘤细胞子集之间的其他差异，我们将比较它们的基因表达谱。