Genetic Predisposition to Chronic Lymphocytic Leukemia (CLL)

慢性淋巴细胞白血病 (CLL) 的遗传倾向

• 批准号: 10590724
• 负责人: Jennifer R Brown
• 金额: $ 66.8万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590724
• 关键词: ATAC-seq; ATM Gene Mutation; ATM gene; Algorithms; Alleles; B-Cell Lymphomas; Biological; Biology; CHEK2 gene; Candidate Disease Gene; Cell Line; Chromatin; Chronic Lymphocytic Leukemia; Clinic; Clinical; Clinical Protocols; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Counseling; DNA Repair Gene; Dana-Farber Cancer Institute; Data; Data Set; Development; Disease; Enrollment; Family; Family Cancer History; Family history of; First Degree Relative; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic study; Genome; Genomics; Germ-Line Mutation; Goals; Grant; Hematologic Neoplasms; Heritability; Hodgkin Disease; Individual; Indolent; Investigation; Literature; Lymphoma; Malignant Neoplasms; Maps; Methodology; Methods; Mutation; Non-Hodgkin' s Lymphoma; North America; Odds Ratio; Pathogenicity; Patients; Population; Population Control; Predisposition; Privatization; Recording of previous events; Registries; Resources; Risk; Risk Factors; Role; Single Nucleotide Polymorphism; Site; Solid Neoplasm; Susceptibility Gene; The Cancer Genome Atlas; Time; Tissue Banks; Transcriptional Regulation; Untranslated RNA; Variant; Work; adult leukemia; ataxia telangiectasia mutated protein; cancer predisposition; cancer type; chronic lymphocytic leukemia cell; cohort; disorder risk; epigenomic profiling; exome sequencing; genetic linkage analysis; genetic testing; genetic variant; genome sequencing; genome wide association study; high risk; improved; malignant breast neoplasm; novel; patient population; patient subsets; polygenic risk score; population based; prospective; protein function; rare variant; risk variant; screening; transcriptome sequencing; tumor; whole genome

Project Summary CLL is the most common leukemia of adults in North America, with about 20,000 new cases per year, and remains incurable. Although a small subset of patients has indolent disease, in the majority of cases CLL is characterized by steady progression toward therapy and once treated, patients are likely to die of the disease or its complications. The primary known risk factor is a family history of the disease, and CLL is one of the most heritable of all cancers, yet the genetic basis of this heritability remains largely unknown. Neither family-based linkage studies nor genomewide association studies (GWAS) have identified clinically useful genetic variants. In our prior work, we hypothesized that the high heritability of CLL may lie in rare germline variants associated with intermediate disease risks, and we identified ATM as the first risk gene for CLL. We further demonstrated that rare germline missense variants in ATM are associated with loss or mutation of the other allele in the tumor, as expected for a cancer predisposition gene. We have since identified these germline ATM variants in 25% of our CLL clinic population, suggesting that ATM may be an important germline driver of CLL. In this grant we will prospectively enroll CLL subjects who have been evaluated for germline ATM variants into a registry that will allow us to determine the association of ATM germline variants with CLL clinical features, development of other cancers and family history of cancer. We will also perform functional assessment of the ATM protein, to determine the impact of the most common and highest risk of these alleles on protein function. Additionally, we will expand the prior analysis that identified ATM, to include all publicly available CLL sequencing data, and employ both a novel highly sensitive variant calling method developed by Google and a novel ancestry matching method. Our preliminary data with this larger cohort and improved methodology have so far confirmed our ATM finding and identified FANCE and CHEK2 as additional CLL risk genes, suggesting a role for other DNA repair genes in CLL susceptibility. We will also focus on higher risk familial CLL with additional exome sequencing, with a similar analysis as above, and with epigenomic profiling with ATAC-seq to explore the non-coding genome. Using a unique cohort of highly impacted families, we will combine ATAC-seq with whole genome and RNA sequencing, to both characterize the gene targets of the GWAS alleles previously identified in CLL, and identify novel noncoding risk variants that impact transcription regulation. This project is feasible because of the rich resources of our unique, well-annotated tissue banks of familial CLL developed over the last 15 years. Our goal with this work is not only to enhance our understanding of the genetic basis of CLL, but also to provide the basis for improved screening and counseling of CLL patients in the clinic, through eventual initiation of clinical trials to assess the utility of genetic testing in this patient population.

项目摘要 CLL是北美成人最常见的白血病，每年约有20，000例新发病例， 并且仍然无法治愈虽然一小部分患者患有无痛性疾病，但在大多数情况下， 其特点是治疗进展稳定，一旦接受治疗，患者很可能死于这种疾病 或其并发症。已知的主要危险因素是疾病的家族史，CLL是最常见的危险因素之一。 所有癌症都是可遗传的，但这种遗传性的遗传基础在很大程度上仍然未知。既不以家庭为基础 连锁研究和全基因组关联研究（GWAS）都已鉴定出临床上有用的遗传变异。 在我们之前的工作中，我们假设CLL的高遗传性可能在于与CLL相关的罕见生殖系变异。 具有中等疾病风险，我们将ATM确定为CLL的第一个风险基因。我们进一步表明 ATM中罕见的种系错义变异与肿瘤中其他等位基因的缺失或突变有关， 正如癌症易感基因所预期的那样。从那以后，我们在25%的人中发现了这些生殖系ATM变异。 这表明ATM可能是CLL的重要生殖细胞驱动因素。在这份协议中，我们 前瞻性招募已接受生殖系ATM变异评估的CLL受试者， 使我们能够确定ATM种系变异与CLL临床特征的关联， 癌症和癌症家族史。我们还将对ATM蛋白进行功能评估， 确定这些等位基因中最常见和最高风险对蛋白质功能的影响。另外我们 将扩大识别ATM的先前分析，以包括所有公开可用的CLL测序数据， 采用了谷歌开发的一种新的高灵敏度变异识别方法和一种新的祖先匹配方法， 法到目前为止，我们对这一较大队列和改进方法的初步数据证实了我们的ATM 发现并鉴定了FANCE和CHEK 2作为额外的CLL风险基因，表明其他DNA修复的作用 CLL易感基因我们还将关注具有额外外显子组测序的高风险家族性CLL， 用与上述类似的分析，并用ATAC-seq的表观基因组谱分析来探索非编码基因组。 使用一个独特的高度影响的家庭队列，我们将联合收割机ATAC-seq与全基因组和RNA结合起来， 测序，以表征先前在CLL中鉴定的GWAS等位基因的基因靶标，并鉴定 影响转录调控的新型非编码风险变体。这个项目是可行的，因为有钱 我们在过去15年中开发的家族性CLL的独特、注释良好的组织库资源。我们的目标 这项工作不仅是为了加强我们对CLL遗传基础的理解，而且也为CLL的治疗提供了基础。 通过最终启动临床试验， 评估基因检测在该患者人群中的效用。