Admixture mapping of mosaic copy number alterations for identification of cancer drivers

用于识别癌症驱动因素的马赛克拷贝数改变的混合图谱

• 批准号: 10608931
• 负责人: Yasminka Aleksandra Jakubek
• 金额: $ 18.13万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608931
• 关键词: Address; Admixture; African; African American; African American population; African ancestry; American; Blood; Cell Fraction; Cells; Cessation of life; Clonal Expansion; Complement; Computing Methodologies; DNA Sequence Alteration; Data; Data Set; Development; Disease; Early Diagnosis; Ensure; European; European ancestry; Frequencies; Funding; Genes; Genetic; Genetic Population Study; Genetic Variation; Genetic study; Genomic Segment; Genomics; Goals; Grant; Haplotypes; Hematologic Neoplasms; Hematology; Human; Incidence; Individual; Inherited; Japanese; Japanese Population; Joints; K22 Award; Latino; Latino Population; Link; Loss of Heterozygosity; Malignant Neoplasms; Maps; Mentors; Methodology; Methods; Minority Groups; Modeling; Molecular; Molecular Profiling; Mosaicism; Mutation; Non-Malignant; Normal tissue morphology; Organism; Paint; Pathologic; Pattern; Persons; Point Mutation; Population; Population Genetics; Prevention; Prevention strategy; Prognosis; Proliferating; Publications; Recurrence; Reporting; Research; Research Personnel; Risk Assessment; Sampling; Screening for cancer; Single Nucleotide Polymorphism; Statistical Methods; Testing; Tissues; Training; Translations; Underrepresented Populations; Variant; Work; Writing; admixture mapping; ancestry analysis; cancer biomarkers; cancer genomics; cancer prevention; cancer risk; cancer seeding; career; detection method; follow-up; genetic variant; genome sequencing; genome wide association study; genomic variation; high risk; improved; innovation; insight; leukemia; method development; mosaic; mosaic analysis; mosaic variant; multi-ethnic; novel; premalignant; programs; skills; translational applications; translational potential; variant detection; whole genome; zygote

PROJECT SUMMARY/ABSTRACT Background: Somatic mosaicism arises due to the clonal expansion of a cell with an acquired mutation, which leads to genetically distinct sub-populations of cells in an organism derived from a single zygote. As a clone proliferates, its subclones can accumulate further molecular changes that seed cancer. A better understanding of acquired point mutations and copy number changes in these clonal expansions can help elucidate the earliest stages of cancer development. Studies of tissues from healthy individuals have found that those with clonal mosaicism in blood, specifically copy number alterations (CNAs), have a ~10-fold higher risk of developing hematological malignancies, thus underscoring the translational potential of mosaicism studies for the development of improved risk assessment and cancer prevention strategies. Research up to now has mainly focused on persons of European ancestry. My own preliminary results show differences in the genomic landscape of CNAs between individuals of African American or Latino ancestry when compared with Europeans. Understanding these differences and the underlying molecular mechanisms is critical in order to include these still under-researched populations in translational mosaicism studies for early detection and prevention of hematological and potentially other cancers. Proposed Research: Aim 1 is to address the great need for comprehensive studies of mosaicism in American minority populations through a large-scale analyses of CNAs in African American and Latino whole genome sequencing (WGS) data sets. This approach will enable a robust comparison of mosaicism profiles across populations; WGS will allow for joint analysis of CNAs and somatic point mutations to gain insights into mechanisms that underlie different rates and subtypes of hematological malignancies across populations. Aim 2 is to develop novel methods to combine CNA and haplotype level ancestry data for detection of variants associated with increased mosaicism rates. I will use these methods to identify genetic variants that are associated with mosaicism and with increased cancer risk in Latinos and African Americans. Candidate: I have led projects to discover and analyze acquired CNAs in thousands of non-malignant tissues – first of their kind studies for pathologically normal and premalignant tissues – as well as in cancer tissues that complement these. This expertise and my established track record in the development of computational methods for human/cancer genomics, will ensure the successful completion of these aims. As larger volumes of normal tissues are molecularly profiled, I will be able to extend methods developed in Aim 2 to additional normal tissue types, and conduct integrative omics analyses. I will follow up this work and the associated publications with an R01 proposal focused on translational applications of mosaic mutations in normal tissues as markers for cancer risk assessment, early detection, and prognosis. The K22 award will be fundamental as I launch my independent investigator career, offering management and grant writing training, helping to hone my skills as a mentor/PI and establish a long-term funded research program.

项目摘要/摘要 背景：体细胞镶嵌物是由于细胞的克隆膨胀而产生的 导致来自单个合子衍生的生物体中细胞的遗传不同的亚群。作为克隆 增殖，其亚克隆可以积累种子癌的进一步分子变化。更好的理解 这些克隆扩展中获得的点突变和拷贝数的变化可以帮助阐明 癌症发展的最早阶段。对健康个体的组织的研究发现 血液中的克隆镶嵌物，特别是拷贝数的变化（CNA），其风险高约10倍 发展血液学恶性肿瘤，从而强调镶嵌研究的转化潜力 改善风险评估和预防癌症的策略的发展。到目前为止的研究 主要专注于欧洲血统的人。我自己的初步结果显示了基因组的差异 相比 欧洲人。了解这些差异和潜在的分子机制对于为了 在翻译的镶嵌研究中包括这些仍未研究的人群，以供早期检测和 预防血液学和潜在的其他癌症。拟议的研究：目标1是解决伟大 通过大规模分析，需要对美国少数群体的镶嵌性进行全面研究 非裔美国人和拉丁裔全基因组测序（WGS）数据集的CNA。这种方法会 可以对种群跨种群的镶嵌概况进行良好的比较； WGS将允许联合分析 CNA和躯体点突变，以深入了解不同速率和亚型的机制 人群之间的血液性恶性肿瘤。目标2是开发新的方法来结合CNA和 单倍型水平的祖先数据，用于检测与镶嵌率提高相关的变体。我会用 这些方法鉴定与镶嵌和癌症相关的遗传变异和癌症风险增加的方法 拉丁裔和非裔美国人。候选人：我领导项目发现和分析获得的CNA 成千上万的非恶性时机 - 首先，用于病理正常和预先陈述的研究 组织 - 以及在癌症组织中补充这些组织。这个专业知识和我已建立的往绩 人类/癌症基因组学计算方法的开发将确保成功完成 这些目的。由于较大的正常组织是分子剖面的，我将能够扩展方法 在AIM 2中开发为其他正常组织类型，并进行综合法分析。我会跟进 这项工作和相关出版物的R01提案着重于马赛克的翻译应用 正常组织中的突变作为癌症风险评估，早期检测和预后的标志。 K22 当我启动我的独立调查员职业，提供管理和格兰特时，奖项将是基本的 写作培训，有助于磨练我作为心理/PI的技能，并建立一项长期资助的研究计划。