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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要背景：体细胞嵌合是由于具有获得性突变的细胞的克隆扩张而产生的，导致来自单个受精卵的生物体中遗传上不同的细胞亚群作为克隆。随着增殖，其亚克隆可以积累进一步的分子变化，从而更好地了解癌症。这些克隆扩增中的获得性点突变和拷贝数变化可以帮助阐明对健康个体组织的研究发现，癌症发展的最早阶段。血液中的克隆嵌合体，特别是拷贝数改变 (CNA)，发生感染的风险大约高 10 倍发展血液恶性肿瘤，从而强调嵌合体研究的转化潜力迄今为止，改进的风险评估和癌症预防策略的发展已经取得了进展。我自己的初步结果主要集中在欧洲血统的人身上。与非裔美国人或拉丁裔血统的个体相比，CNA 的情况欧洲人了解这些差异及其潜在的分子机制对于将这些尚未充分研究的人群纳入转化嵌合研究中，以便及早发现和预防血液癌症和潜在的其他癌症：目标 1 是解决重大问题。需要通过大规模分析对美国少数群体中的镶嵌现象进行全面研究该方法将在非裔美国人和拉丁裔全基因组测序 (WGS) 数据集中进行 CNA 分析。能够对不同人群的嵌合体概况进行强有力的比较，从而能够进行联合分析； CNA 和体细胞点突变可深入了解不同速率和亚型背后的机制目标 2 是开发结合 CNA 和血液恶性肿瘤的新方法。我将使用单倍型水平祖先数据来检测与嵌合率增加相关的变异。这些方法可识别与嵌合体和癌症风险增加相关的遗传变异拉丁裔和非裔美国人：我领导过一些项目来发现和分析获得的 CNA。数千个非恶性组织——首次针对病理正常和癌前组织进行此类研究组织——以及补充这些的癌症组织。人类/癌症基因组学计算方法的开发将确保成功完成随着对更大体积的正常组织进行分子分析，我将能够扩展方法。在目标 2 中开发了额外的正常组织类型，并进行综合组学分析，我将跟进。这项工作以及与 R01 提案相关的出版物，重点关注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记。当我开始我的独立调查员职业生涯时，该奖项将至关重要，提供管理和资助写作培训，帮助磨练我作为导师/PI 的技能，并建立长期资助的研究计划。