Genetic Predisposition to Chronic Lymphocytic Leukemia (CLL)

项目摘要 慢性淋巴细胞性白血病是北美最常见的成人白血病，每年约有2万例新发病例， 仍然是不治之症。尽管有一小部分患者患有惰性疾病，但在大多数情况下，CLL 以稳步向治疗进发为特征，一旦接受治疗，患者很可能死于这种疾病。 或者它的复杂性。已知的主要危险因素是疾病的家族史，慢性淋巴细胞性白血病是最常见的危险因素之一。 在所有癌症中都是可遗传的，但这种遗传性的遗传基础在很大程度上仍不清楚。既不是基于家庭的 连锁研究或全基因组关联研究(GWAS)都已确定了临床上有用的遗传变异。 在我们之前的工作中，我们假设CLL的高遗传性可能存在于相关的罕见生殖系变异中。 具有中等疾病风险，我们确定ATM是CLL的第一个风险基因。我们进一步展示了 ATM中罕见的生殖系错义变异与肿瘤中另一个等位基因的丢失或突变有关， 正如人们对癌症易感基因的预期。自那以后，我们在25%的人中发现了这些生殖系ATM变体 我们的CLL临床人群，提示ATM可能是CLL的重要种系驱动因素。在这笔赠款中，我们将 前瞻性地将已接受生殖系ATM变异评估的CLL受试者登记到将 使我们能够确定ATM胚系变异与CLL临床特征、其他 癌症和癌症家族史。我们还将对ATM蛋白进行功能评估，以 确定这些等位基因中最常见和风险最高的基因对蛋白质功能的影响。此外，我们 将扩展识别ATM的先前分析，以包括所有公开可用的CLL测序数据，以及 使用Google开发的新的高度敏感的变体调用方法和新的血统匹配方法 方法。到目前为止，我们与这个更大的队列和改进的方法的初步数据证实了我们的自动取款机 发现并确认Fance和CHEK2是额外的CLL风险基因，提示其他DNA修复也有作用 慢性淋巴细胞性白血病易感基因。我们还将通过额外的外显子测序来关注高风险家族性CLL， 用与上面类似的分析，并用ATAC-SEQ进行表观基因组图谱来探索非编码基因组。 利用一个独特的高影响家族队列，我们将把atac-seq与全基因组和rna结合起来。 测序，以表征先前在CLL中识别的GWAS等位基因的基因靶标，并识别 影响转录调控的新的非编码风险变体。这个项目是可行的，因为有了 我们独特的、注解良好的家族性CLL组织库资源在过去15年中发展起来。我们的目标 这项工作不仅是为了增进我们对CLL的遗传学基础的认识，也是为CLL的研究提供依据 通过最终启动临床试验，改善临床上CLL患者的筛查和咨询 评估基因检测在这一患者群体中的效用。

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.