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.

项目概要 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。尽管一小部分患者患有惰性疾病，但在大多数情况下 CLL 其特点是治疗稳步进展，一旦治疗，患者很可能死于该病 或其并发症。已知的主要危险因素是该疾病的家族史，CLL 是最常见的危险因素之一。 所有癌症均可遗传，但这种遗传性的遗传基础仍然很大程度上未知。既不以家庭为基础 连锁研究和全基因组关联研究 (GWAS) 均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 的高遗传力可能在于与相关的罕见种系变异 具有中等疾病风险，我们将 ATM 确定为 CLL 的第一个风险基因。我们进一步证明了 ATM 中罕见的种系错义变异与肿瘤中其他等位基因的丢失或突变有关， 正如癌症易感基因所预期的那样。此后，我们在 25% 的病例中发现了这些种系 ATM 变异。 我们的 CLL 诊所人群表明 ATM 可能是 CLL 的重要种系驱动因素。在这笔赠款中，我们将 前瞻性地将已接受种系 ATM 变异评估的 CLL 受试者纳入注册表，该注册表将 使我们能够确定 ATM 种系变异与 CLL 临床特征、其他疾病发展的关联 癌症和癌症家族史。我们还将对 ATM 蛋白进行功能评估，以 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。此外，我们 将扩展之前确定 ATM 的分析，以包括所有公开可用的 CLL 测序数据，以及 采用谷歌开发的新颖的高度敏感的变体调用方法和新颖的祖先匹配 方法。到目前为止，我们通过更大的队列和改进的方法获得的初步数据已经证实了我们的 ATM 发现并确定 FANCE 和 CHEK2 为额外的 CLL 风险基因，表明其他 DNA 修复的作用 CLL 易感性基因。我们还将通过额外的外显子组测序来关注高风险的家族性 CLL， 进行与上述类似的分析，并使用 ATAC-seq 进行表观基因组分析来探索非编码基因组。 利用一组受到高度影响的独特家族，我们将 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异。这个项目可行，因为有钱 我们独特的、注释明确的家族性 CLL 组织库资源是在过去 15 年中开发的。我们的目标 这项工作不仅增强了我们对CLL遗传基础的认识，也为我们提供了依据 通过最终启动临床试验来改善临床 CLL 患者的筛查和咨询 评估基因检测在该患者群体中的效用。