Integration of germline and tumor genomes in CLL

CLL 中种系和肿瘤基因组的整合

基本信息

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
项目类别：
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

项目摘要

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.

项目概要：慢性淋巴细胞白血病 (CLL) 是 B 细胞淋巴细胞的肿瘤。它有很强的遗传成分通过全基因组关联研究鉴定出 45 个遗传性单核苷酸多态性 (SNP) （GWAS）。使用这些 SNP，我们计算了多基因风险评分 (PRS)，它是跨 SNP 的风险等位基因，权重是 SNP 关联的对数比值比，并发现与中间五分之一的个体相比，位于上五分之一的个体患 CLL 的风险增加了约 3 倍 (P<0.0001)，提供证据表明已知和常见 CLL 易感性变异的组合是其中之一最强的 CLL 危险因素。此外，全基因组和外显子组测序研究最近已鉴定出 60 多种复发性体细胞 CLL 变异或拷贝数改变 (CNA)，并发现 88-90% CLL 病例至少具有一种假定的驱动突变，约 44% 具有至少三种驱动突变。然而，关于遗传性基因变异如何与肿瘤相互作用（在 DNA 和 RNA 水平）及其作用，人们知之甚少。对肿瘤进化的贡献。该应用程序旨在解决这一知识差距。初步数据显示从我们的 CLL GWAS 中，我们有证据表明，一些 CLL GWAS 发现的 SNP 会影响使用来自全血或的 RNA 顺式（在 SNP 周围 1 Mb 窗口内）基因的表达水平类淋巴母细胞系（LCL）。然而，由于全血是多种细胞类型的组合物，其中 B 细胞占约 5-10%，B 细胞特异性信号最有可能被遗漏，并且细胞的基因表达用于生成 LCL 的 Epstein Barr 病毒转化可能会改变线路。目标 1 建议通过使用来自分选的肿瘤 B 细胞、健康对照的分选 B 细胞的 RNA 克服了这些限制，并且从患有 CLL（单克隆 B 细胞淋巴细胞增多症）先兆病症的个体中分选克隆 B 细胞 (MBL)，进行表达数量性状基因座 (eQTL) 分析。体外验证和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，小是了解具有体细胞驱动突变的个体中遗传种系变异的程度。目标2 将填补这一空白，以评估种系和肿瘤 DNA 变异之间的关系，并评估它们的对 CLL 结果的影响。最后，CLL 是一种异质性疾病，约 20% 的 CLL 病例有 5 年的病程总生存率为15-19%。有许多体细胞变异会导致侵袭性 CLL 疾病，但很少有人们知道遗传变异的作用。目标 3 将通过识别新的遗传变异来解决这一差距与 CLL 侵袭性相关。完成后，我们将确定已知 CLL 的基因靶标易感性 SNP，将表征那些具有高或低基因组变异负担的 CLL 病例，评估了对 CLL 结果的影响，并将深入了解遗传对侵袭性的贡献慢性淋巴细胞白血病。我们的结果可能为靶向治疗提供新的生物标志物的潜在发现，揭示新的对 CLL 进行细分的方法，并为家庭成员制定潜在的遗传咨询策略。