Integration of germline and tumor genomes in CLL

CLL 中种系和肿瘤基因组的整合

• 批准号: 10527324
• 负责人: Esteban Braggio
• 金额: $ 62.22万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527324
• 关键词: Address; Affect; Apoptosis; B-Cell Neoplasm; B-Lymphocytes; Biological; Biology; CD19 gene; CISH gene; Cell Line; Characteristics; Chronic Lymphocytic Leukemia; Classification; DNA; DNA purification; Data; Development; Diagnosis; Disease; Epigenetic Process; Etiology; Evolution; Family member; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Counseling; Genetic Transcription; Genome; Genomics; Genotype; Germ-Line Mutation; 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; Sorting; Susceptibility Gene; Telomere Length Maintenance; Testing; Time; Validation; Variant; Weight; Whole Blood; Woman; cancer genome; cell type; driver mutation; early screening; exome sequencing; genetic variant; genome sequencing; genome wide association study; improved; insight; leukemia; lymphoblastoid cell line; men; novel; novel marker; polygenic risk score; risk variant; targeted sequencing; targeted treatment; trait; transcriptome sequencing; transcriptomics; transforming virus; tumor; tumor DNA; variant of interest; 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.

项目总结： 慢性淋巴细胞白血病(CLL)是一种B淋巴细胞肿瘤。它有很强的遗传成分 全基因组关联研究发现了45个遗传性单核苷酸多态(SNPs) (GWAS)。使用这些SNP，我们计算了多基因风险得分(PRS)，这是 SNP的风险等位基因，权重是来自SNP关联的对数优势比，并发现 上五分之一的人患慢性淋巴细胞性白血病的风险是中五分之一的人的~3倍 (P&lt；0.0001)，提供了已知和常见的CLL易感性变异的组合是一种的证据 最强的慢性淋巴细胞性白血病风险因素。此外，全基因组和外显子组测序研究最近 发现了60多个反复发生的体细胞CLL变异或拷贝数改变(CNA)，并发现88%-90%的 CLL病例至少有一个假定的驱动程序突变，~44%的患者至少有三个驱动程序突变。然而， 关于遗传的遗传变异如何与肿瘤相互作用(在DNA和RNA水平)以及它们的作用，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鸿沟。在初步数据中 从我们的CLL GWAS，我们有证据表明，CLL GWAS发现的一些SNPs影响着 使用来自全血的RNA或在SNP周围的1-Mb窗口内的顺式基因表达水平 淋巴母细胞样细胞系(LCL)。然而，因为全血是由多种细胞类型组成的，所以 哪些B细胞占~5%-10%，B细胞特异性信号很可能被遗漏，来自细胞的基因表达 线条可能被用于产生LCL的Epstein Barr病毒转化而改变。目标1建议 通过使用分选的肿瘤B细胞、健康对照的分选B细胞和 从具有CLL、单克隆性B细胞增多症前体条件的个体中分离克隆B细胞 (MBL)，进行表达数量性状基因座(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。下一步，很少是 已知携带体细胞驱动基因突变个体的遗传生殖系变异的程度。目标2 将解决这一差距，以评估生殖系和肿瘤DNA变异之间的关系，并评估它们的 对慢性淋巴细胞白血病预后的影响。最后，CLL是一种异质性疾病，约20%的CLL病例有5年的 总体存活率为15%-19%。有许多体细胞变异会导致侵袭性CLL疾病，但很少有 已知遗传变异的作用。目标3将通过识别新的遗传变异来解决这一差距 与CLL攻击性相关。完成后，我们将确定已知的CLL的基因靶点 易感性SNPs，将具有高或低基因组变异和低负担的CLL病例的特征 评估了对慢性淋巴细胞白血病结局的影响，并将深入了解遗传因素对攻击性的影响 CLL.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 如何细分慢性淋巴细胞性白血病，并为家庭成员开发潜在的遗传咨询策略。

项目成果

The CLL International Prognostic Index predicts outcomes in monoclonal B-cell lymphocytosis and Rai 0 CLL.

• DOI: 10.1182/blood.2020009813
• 发表时间: 2021-07-15
• 期刊: Blood
• 影响因子: 20.3
• 作者: Parikh SA;Rabe KG;Kay NE;Call TG;Ding W;Leis JF;Kenderian SS;Muchtar E;Wang Y;Koehler AB;Schwager SM;Lesnick CE;Kleinstern G;Van Dyke D;Hanson CA;Braggio E;Slager SL;Shanafelt TD
• 通讯作者: Shanafelt TD