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

项目摘要/摘要 背景：体细胞嵌合体的产生是由于带有获得性突变的细胞的克隆性扩张，这是 导致来自单个受精卵的有机体中遗传上不同的细胞亚群。作为克隆人 增殖时，其亚克隆会积累进一步的分子变化，从而导致癌症的发生。更好地理解 这些克隆扩增中获得性点突变和拷贝数的变化有助于阐明 癌症发展的最早阶段。对健康个体组织的研究发现，那些患有 血液中的克隆性嵌合体，特别是拷贝数改变(CNA)，患上这种疾病的风险要高10倍。 发展为血液系统恶性肿瘤，从而强调嵌合体研究的翻译潜力 制定改进的风险评估和癌症预防战略。到目前为止的研究已经 主要集中在欧洲血统的人。我自己的初步结果显示了基因组上的差异 非洲裔美国人或拉丁裔美国人之间的CNA景观 欧洲人。了解这些差异和潜在的分子机制对于 将这些仍未被研究的群体纳入翻译嵌合体研究，以便早期发现和 预防血液病和潜在的其他癌症。建议的研究：目标1是解决 需要通过大规模分析来全面研究美国少数族裔人口中的马赛克 在非洲裔美国人和拉丁裔全基因组测序(WGS)数据集中的CNA。这一方法将 实现不同种群间镶嵌特征的可靠比较；WGS将允许联合分析 CNAS和体细胞点突变以深入了解不同比率和亚型背后的机制 血液系统恶性肿瘤在人群中的发病率。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，用于检测与增加的嵌合率相关的变异。我会用 这些方法可以识别与嵌合体和癌症风险增加相关的基因变异 拉丁裔和非裔美国人。应聘者：我曾领导过发现和分析收购的CNA的项目 数以千计的非恶性组织-第一次对病理正常和癌前病变进行研究 组织--以及与之相辅相成的癌症组织。这方面的专业知识和我在 人类/癌症基因组学计算方法的发展，将确保成功完成 这些目标。随着更大体积的正常组织被分子图谱分析，我将能够扩展方法 在目标2中开发，以增加正常组织类型，并进行综合组学分析。我会跟进的 这项工作和与R01提案相关的出版物侧重于马赛克的翻译应用 正常组织中的突变可作为癌症风险评估、早期检测和预后的标志。K22 奖励将是我开始独立调查员职业生涯的基础，提供管理和拨款 写作培训，帮助磨练我作为导师/PI的技能，并建立一个长期资助的研究计划。

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.