Integration of germline and tumor genomes in CLL

CLL 中种系和肿瘤基因组的整合

• 批准号: 10059186
• 负责人: Esteban Braggio
• 金额: $ 63.91万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-06 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059186
• 关键词: Address; Affect; Apoptosis; B-Cell Neoplasm; B-Lymphocytes; Biological; Biology; CD19 gene; CISH gene; Cell Line; Characteristics; Chronic Lymphocytic Leukemia; DNA; Data; Development; Diagnosis; Disease; Epigenetic Process; Etiology; Evolution; Family member; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Counseling; Genetic Transcription; Genome; Genomics; Genotype; Goals; Heterogeneity; Human Herpesvirus 4; In Vitro; Individual; Inherited; Joints; Knowledge; Location; Lymphocyte; Lymphocytosis; MicroRNAs; Mutate; Odds Ratio; Outcome; Patients; Predisposition; Prevention strategy; Public Health; Quantitative Trait Loci; RNA; Recurrence; Risk; Risk Factors; Role; Signal Transduction; Single Nucleotide Polymorphism; Somatic Mutation; Susceptibility Gene; Telomere Length Maintenance; Testing; Time; Validation; Variant; Weight; Whole Blood; Woman; base; cancer genome; cell type; chronic lymphocytic leukemia cell; driver mutation; early screening; exome sequencing; genetic variant; genome sequencing; genome wide association study; improved; insight; interest; leukemia; lymphoblastoid cell line; men; novel; novel marker; polygenic risk score; risk variant; targeted sequencing; targeted treatment; trait; transcriptome sequencing; transcriptomics; tumor; tumor DNA; whole genome

Project Summary: Chronic lymphocytic leukemia (CLL) is a neoplasm of B-cell lymphocytes. It has a strong genetic component with 45 inherited single nucleotide polymorphisms (SNPs) identified through genome-wide association studies (GWAS). Using these SNPs, we computed a polygenic risk score (PRS), which is a weighted average of the risk alleles across the SNPs with the weights being the log odds ratios from SNP associations, and found that individuals in the upper quintile had a ~3-fold increased risk of CLL compared to the middle quintile (P<0.0001), providing evidence that the combination of known and common CLL susceptibility variants is one of the strongest CLL risk factors. In addition, whole genome and exome sequencing studies have recently identified over 60 recurrent somatic CLL variants or copy number alterations (CNA) and found that 88-90% of CLL cases have at least one putative driver mutation and ~44% have at least three driver mutations. However, little is known about how the inherited genetic variants interact with the tumor (at DNA and RNA level) and their contribution to tumor evolution. This application proposes to address this knowledge gap. In preliminary data from our CLL GWAS, we have evidence that a number of the CLL GWAS-discovered SNPs influence the expression levels of genes in cis (within 1-Mb window around the SNP) using RNA from whole blood or lymphoblastoid cell lines (LCL). However, because whole blood is a composition of multiple cell types, of which B-cells make up ~5-10%, B-cell specific signals are most likely missed, and gene expression from cell lines may be altered by the Epstein Barr Virus transformation used to generate LCL. Aim 1 proposes to overcome these limitations by using RNA from sorted tumor B-cells, sorted B-cells of healthy controls, and sorted clonal B-cells from individuals with the precursor condition to CLL, monoclonal B-cell lymphocytosis (MBL), to perform expression quantitative trait locus (eQTL) analyses. Validation and experimental in vitro studies will be performed to confirm and evaluate the functional relevance of variants of interest. Next, little is known about the extent of inherited germline variants in the individuals with somatic driver mutations. Aim 2 will address this gap to assess the relationship between germline and tumor DNA variants and to assess their effect on CLL outcomes. Finally, CLL is a heterogeneous disease with ~20% of CLL cases having a 5-year overall survival of 15-19%. There are a number of somatic variants that drive aggressive CLL disease, yet little is known about the role of inherited variants. Aim 3 will address this gap by identifying novel inherited variants associated with CLL aggressiveness. Upon completion, we will have identified gene targets of the known CLL susceptibility SNPs, will have characterized those CLL cases with high or low burden of genomic variants and assessed the effects on CLL outcomes, and will have gained insight into the genetic contribution to aggressive CLL. Our results may provide the potential discovery of novel biomarkers for targeted therapies, reveal novel ways to subclassify CLL, and develop potential genetic counseling strategies for family members.

项目摘要： 慢性淋巴细胞性白血病（CLL）是B细胞淋巴细胞的肿瘤。它具有强大的遗传成分 通过45种遗传的单核苷酸多态性（SNP），通过全基因组关联研究确定 （GWAS）。使用这些SNP，我们计算了多基因风险评分（PRS），这是 跨SNP的风险等位基因，重量是SNP关联的对数赔率比率，并发现 与中间五分之一相比 （p <0.0001），提供证据表明已知和常见的CLL敏感性变体的组合是一种 最强的CLL风险因素。此外，整个基因组和外显子组测序研究最近已有 确定了60多个经常性的体细胞CLL变体或拷贝数变化（CNA），发现88-90％ CLL病例至少具有一个假定的驱动突变，约有44％的驱动因素至少有三个驱动器突变。然而， 关于遗传的遗传变异如何与肿瘤（在DNA和RNA水平）及其相互作用的知之甚少 对肿瘤进化的贡献。该应用程序建议解决此知识差距。在初步数据中 从我们的CLL GWAS中，我们有证据表明，许多CLL GWA被发现的SNP会影响 使用全血的RNA或 淋巴母细胞系（LCL）。但是，由于全血是多种细胞类型的组成，所以 哪些B细胞占〜5-10％，B细胞特异性信号很可能被遗漏，并且来自细胞的基因表达 用来产生LCL的爱泼斯坦Barr病毒转化可能会改变线。目标1提议 通过使用分类的肿瘤B细胞，健康对照的B细胞和 从具有前体条件到CLL的个体，单克隆B细胞淋巴细胞增多的个体分类的克隆B细胞 （MBL），执行表达定量性状基因座（EQTL）分析。验证和体外实验 将进行研究以确认和评估感兴趣的变体的功能相关性。接下来，几乎没有 知道具有体细胞驱动突变的个体中遗传性种系变异的程度。目标2 将解决这一差距，以评估种系与肿瘤DNA变体之间的关系并评估其 对CLL结果的影响。最后，CLL是一种异质性疾病，约有20％的CLL病例患有5年 总生存率为15-19％。有许多躯体变体会导致侵略性的CLL疾病，但很少 已经知道遗传变体的作用。 AIM 3将通过识别新颖的继承变体来解决这一差距 与CLL侵略性相关。完成后，我们将确定已知CLL的基因靶标 敏感性SNP将表征那些具有基因组变体负担高或低负担的CLL病例，并且 评估对CLL结果的影响，并将深入了解对侵略性的遗传贡献 Cll。我们的结果可能为靶向疗法提供了新型生物标志物的潜在发现，揭示了新颖的生物标志物 将CLL分类并为家庭成员制定潜在的遗传咨询策略的方法。