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: 10181439
• 负责人: Jennifer R Brown
• 金额: $ 67.83万
• 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/10181439
• 关键词: ATAC-seq; ATM Gene Mutation; ATM gene; Algorithms; Alleles; B-Cell Lymphomas; Biological; Biology; CHEK2 gene; Cancer Family; 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 Predisposition to Disease; Genetic study; Genome; Genomics; Goals; Grant; Hematologic Neoplasms; Heritability; Hodgkin Disease; Individual; Indolent; Institutes; Investigation; Literature; Lymphoma; Malignant Neoplasms; 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; XCL1 gene; adult leukemia; ataxia telangiectasia mutated protein; base; cancer predisposition; cancer type; chronic lymphocytic leukemia cell; cohort; disorder risk; epigenomics; 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是北美最常见的成年人白血病，每年约有20,000例新病例， 并保持无法治愈。尽管一小部分患者患有懒惰的疾病，但在大多数情况下CLL 以稳定的治疗进展，一旦接受治疗，患者可能死于该疾病 或它的并发症。已知的主要危险因素是该疾病的家族史，CLL是最重要的危险因素。 在所有癌症中都可以遗传，但是这种遗传力的遗传基础在很大程度上仍然未知。都不是基于家庭的 连锁研究或全基因组关联研究（GWAS）已确定临床上有用的遗传变异。 在我们先前的工作中，我们假设CLL的高遗传力可能在于罕见的种系变体 有中间疾病的风险，我们确定ATM是CLL的第一个风险基因。我们进一步证明了 ATM中罕见的种系错线变体与肿瘤中其他等位基因的丢失或突变有关， 如预期的癌症易感基因。此后，我们在25％的 我们的CLL诊所人口，表明ATM可能是CLL的重要种系驱动器。在这笔赠款中，我们将 未来将已评估的种系ATM变体评估的CLL主题注册为注册表 允许我们确定ATM种系变体与CLL临床特征的关联，其他 癌症和癌症家族史。我们还将对ATM蛋白进行功能评估， 确定这些等位基因最常见和最高风险对蛋白质功能的影响。另外，我们 将扩展确定ATM的先前分析，包括所有公开可用的CLL测序数据，以及 使用Google开发的一种新颖的高度敏感变体呼叫方法和一种新颖的血统匹配 方法。到目前为止 查找和识别fance和chek2是附加的CLL风险基因，这表明其他DNA修复的作用 CLL敏感性中的基因。我们还将专注于更高风险的家族性CLL，并进行其他外显子组测序， 具有与上述类似的分析，并具有ATAC-SEQ的表观分析，以探索非编码基因组。 使用独特的高度影响家庭的队列，我们​​将将ATAC-SEQ与整个基因组和RNA相结合 测序，以表征先前在CLL中鉴定的GWAS等位基因的基因靶标，并识别 影响转录调节的新型非编码风险变体。这个项目是可行的，因为富人 在过去的15年中，我们独特的，井井有条的家庭CLL组织库的资源。我们的目标 这项工作不仅是为了增强我们对CLL遗传基础的理解，而且还提供了基础 通过最终启动临床试验，以改善诊所中CLL患者的筛查和咨询 评估该患者人群基因检测的效用。