Integrating Clues from the Somatic Genome in the Search for Rare Germline Cancer Susceptibility Variants

整合体细胞基因组的线索来寻找罕见的种系癌症易感性变异

• 批准号: 10159876
• 负责人: Thomas Louis LaFramboise
• 金额: $ 18.82万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-06 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159876
• 关键词: Acute Myelocytic Leukemia; Alleles; Allelic Imbalance; Back; Biological; Biological Assay; Candidate Disease Gene; Case-Control Studies; Clinical Management; Collection; Counseling; DNA; DNA Sequence; Data; Data Collection; Data Set; Development; Diagnostic; Disease; Disease susceptibility; Dysmyelopoietic Syndromes; Early Diagnosis; Event; Exploratory/Developmental Grant; Family; General Population; Genes; Genome; Genomics; Goals; Haplotypes; Heritability; Human; Human Genome; Inherited; JAK2 gene; Lead; Lesion; Malignant Neoplasms; Methodology; Mutation; Myeloproliferative disease; Pathway interactions; Patients; Penetrance; Physicians; Population Study; Predisposition; Publications; Reporting; Research Personnel; Resistance; Risk; Sample Size; Signal Transduction; Somatic Mutation; Susceptibility Gene; System; Testing; Validation; Variant; Work; base; cancer type; case control; causal variant; cohort; epigenetic regulation; exome; experimental study; feasibility testing; gain of function; genetic variant; genome wide association study; genome-wide; genomic data; new therapeutic target; novel; novel therapeutics; population based; risk variant; screening; success; synergism; tool; treatment response; tumor; tumor DNA; tumor initiation

Project Summary/Abstract It is well-established that human cancer has a substantial heritable component. However, studies have thus far only been able to pinpoint a portion of the germline contribution. The hypothesis underpinning this proposal is that genes and alleles that contribute to cancer susceptibility may be revealed using clues from the somatic genome. Specifically, the focus of the project will be to develop a battery of statistical tests that will query large sequencing data sets from patient paired tumor-normal genomes for signals of synergy between the genomic variants in the two genomes. As part of the proposed work, the project will focus on myeloid malignancy to demonstrate the system's efficacy. Toward this end, the project will pursue three Specific Aims: 1. Develop and apply statistical tests to paired whole-exome data from thousands of myeloid malignancy patients to identify genes/alleles that show signals of germline-somatic synergy. a) Query for genes in which germline and somatic events co-occur statistically frequently b) Query for genes in which germline and somatic events are statistically mutually exclusive c) Identify genes in which disruptive germline alleles are preferentially promoted over wild-type in chromosomal allelic imbalance events 2. Query germline DNA and tumor expression data for genes expressing the variant germline allele over wild-type in the tumor. 3. Expand findings in Aims 1 and 2 to a case-control study. Large in-house, public, and collaborator genomic data sets from thousands of patients will be used to statistically assess germline-somatic synergy. Genes showing such signals of synergy will then be subjected to a large case- control study, under the hypothesis that the genes/alleles identified using clues from the somatic genome will emerge as disease susceptibility loci. Ultimately, identifying inherited risk variants would have profound implications for diagnostics, clinical management, and counseling. A panel of known susceptibility variants could be incorporated into screening assays, which would serve as tools to inform physicians and their patients of elevated risk. This could result in a higher level of surveillance, enabling early detection and more informed counselling for families carrying the risk variants. Additionally, researchers would have a better picture of the gene and pathway disruptions that lead to tumor development and resistance, eventually having the potential of finding new druggable targets for these diseases, yielding new therapeutics.

项目概要/摘要 众所周知，人类癌症具有显着的遗传成分。然而，迄今为止的研究表明 只能查明生殖系贡献的一部分。支持该提议的假设是 利用来自体细胞的线索可以揭示导致癌症易感性的基因和等位基因 基因组。具体来说，该项目的重点将是开发一系列统计测试，以查询大量数据 对患者配对的肿瘤-正常基因组的数据集进行测序，以获取基因组之间的协同信号 两个基因组中的变异。作为拟议工作的一部分，该项目将重点关注骨髓恶性肿瘤 展示系统的功效。为此，该项目将追求三个具体目标： 1. 开发统计测试并将其应用于来自数千种骨髓恶性肿瘤的配对全外显子组数据 患者识别显示种系-体细胞协同信号的基因/等位基因。 a) 查询种系事件和体细胞事件在统计上频繁同时发生的基因 b) 查询种系事件和体细胞事件在统计上互斥的基因 c) 鉴定其中破坏性种系等位基因比野生型优先促进的基因 染色体等位基因失衡事件 2. 查询种系 DNA 和肿瘤表达数据，以查找表达变异种系等位基因的基因 肿瘤中的野生型。 3. 将目标 1 和 2 中的发现扩展到病例对照研究。 来自数千名患者的大型内部、公共和合作者基因组数据集将用于统计 评估种系-体细胞协同作用。显示出这种协同信号的基因将受到很大的影响—— 对照研究，假设使用体细胞基因组线索识别的基因/等位基因将 作为疾病易感位点出现。 最终，识别遗传风险变异将对诊断、临床产生深远的影响。 管理、咨询等。一组已知的易感性变异可以纳入筛选 检测，这将作为告知医生及其患者风险升高的工具。这可能会导致 更高水平的监测，能够及早发现并为有风险的家庭提供更明智的咨询 变种。此外，研究人员可以更好地了解导致疾病的基因和通路破坏。 肿瘤的发展和耐药性，最终有可能为这些肿瘤找到新的药物靶标 疾病，从而产生新的治疗方法。