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Impact of germline variants on racial and ethnic differences in somatic mutation frequency

种系变异对体细胞突变频率的种族和民族差异的影响

基本信息

批准号：
10372129
负责人：
Amanda Ewart Toland
金额：
$ 34.97万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10372129
关键词：
Affect African American population Alleles Asian Asian population Automobile Driving Biological Breast CRISPR/Cas technology Cells Colon Colorectal Cancer DNA Sequence Alteration Data Data Set Development Environmental Exposure Ethnic group Event Frequencies Genes Genetic Genotype Goals Head and Neck Squamous Cell Carcinoma Head and neck structure Human In Vitro Individual Inherited KRAS2 gene Knock-in Knock-out Lead Malignant Neoplasms Measures Methodology Mus Mutation Not Hispanic or Latino Outcome PIK3CA gene Pathway interactions Phenotype Population Prevalence Prevention strategy Prognosis Race Role Smoking Somatic Mutation Susceptibility Gene TP53 gene Testing The Cancer Genome Atlas Tumor Biology Variant Woman aurora kinase A cancer health disparity cancer risk design driver mutation ethnic difference functional genomics gain of function genetic variant genomic data in vitro Model in vivo innovation malignant breast neoplasm new therapeutic target novel novel therapeutic intervention public health relevance racial difference racial disparity risk variant screening skin squamous cell carcinoma socioeconomics tumor tumor growth tumorigenesis

项目摘要

Summary Tumor sequencing data have revealed significant differences in mutation frequencies between racial and ethnic groups. Some of these differences can be attributed to environmental exposure, such as smoking frequency, but disparities persist even after adjustment for known factors. Well-described examples include TP53 mutations that are seen at elevated rates in breast cancers in African-Americans compared to Asian and non-Hispanic White women and KRAS mutations that are observed in higher rates in colorectal cancers from African-Americans relative to other racial groups. As cancer aggressiveness and survival can depend on what pathways are perturbed in a tumor, the frequency at which a cancer driver mutation occurs in a population should influence some of the observed racial disparities in outcomes. Emerging data from our lab and others suggest that germline genetic variants impact somatic events in tumors. We identified associations between AURKA variants and TP53 in head and neck squamous cell carcinomas from The Cancer Genome Atlas. We found that individuals with at least one AURKA allele previously associated with cancer risk were more likely to have gain-of-function TP53 mutations relative to individuals homozygous for the non-risk associated allele. These and other studies suggest an association between germline Genetic variants and somatic Mutations (GxM) in tumor development. This study will search for novel Genetic variants associated with TP53, PIK3CA, and KRAS Mutations in order to explain racial differences in tumor biology. In this study, we will test the innovative hypothesis that germline genetic variants that differ in frequency between racial groups drive the observed racial differences in frequency of somatic mutations. Our goals are to understand the association between somatic mutations, germline genetic variants and tumorigenesis in racial disparities, and to determine the biological impact of GxM associations on cancer phenotypes using in vitro models. Using existing genotype and mutation data, these goals will be accomplished in two aims: 1. To identify and characterize GxM associations for TP53 and PIK3CA mutations in breast cancer in order to understand how germline variants drive racial differences in somatic mutation frequency. Variants found in GxM association studies from 3700 individuals with breast cancer will be evaluated in 4000 additional breast cancer cases from multiple racial and ethnic groups. Top GxM interactions will be assessed functionally using CRISPR/Cas9 to create knock-in and knock-out mutations and alleles. 2. To identify and characterize GxM associations for KRAS mutations in colorectal cancer (CRC) using a similar approach in Aim 1. These studies will apply a novel concept to discover new biological drivers for racial disparities in cancer outcomes, as measured by mutation frequencies. Results from this study have the potential to inform mechanistic studies which, in turn, will lead to new therapeutic strategies for cancers showing racial differences in mutation frequency and outcome.

概括肿瘤测序数据揭示了种族和种族之间突变频率的显着差异族裔群体。其中一些差异可归因于环境暴露，例如吸烟频率，但即使在调整已知因素后，差异仍然存在。详细描述的例子包括与亚洲人和亚洲人相比，非洲裔美国人的乳腺癌中 TP53 突变的发生率更高非西班牙裔白人女性和 KRAS 突变在结直肠癌中的发生率较高非裔美国人相对于其他种族群体。由于癌症的侵袭性和生存率取决于什么肿瘤中的通路受到干扰，即人群中癌症驱动突变发生的频率应该会影响一些观察到的结果中的种族差异。来自我们实验室和其他实验室的新数据表明种系遗传变异影响肿瘤中的体细胞事件。我们确定了之间的关联癌症基因组图谱中头颈鳞状细胞癌中的 AURKA 变异和 TP53。我们发现至少具有一个先前与癌症风险相关的 AURKA 等位基因的个体更有可能相对于非风险相关等位基因纯合的个体，具有功能获得性 TP53 突变。这些和其他研究表明种系遗传变异与体细胞突变之间存在关联（GxM）在肿瘤发展中的作用。本研究将寻找与 TP53、PIK3CA、和 KRAS 突变，以解释肿瘤生物学中的种族差异。在本研究中，我们将测试创新假设认为，种族群体之间频率不同的种系遗传变异驱动着观察到体细胞突变频率的种族差异。我们的目标是了解协会体细胞突变、种系遗传变异和种族差异中的肿瘤发生之间的关系，并确定使用体外模型研究 GxM 关联对癌症表型的生物学影响。使用现有基因型和突变数据，这些目标将通过两个目标来实现： 1. 识别和表征 GxM TP53 和 PIK3CA 突变与乳腺癌的关联，以了解种系变异如何驱动体细胞突变频率的种族差异。 GxM 关联研究中发现的 3700 个变体将对来自多个种族和地区的另外 4000 例乳腺癌患者进行评估族裔群体。将使用 CRISPR/Cas9 对顶级 GxM 相互作用进行功能评估，以创建基因敲入和敲除突变和等位基因。 2. 鉴定和表征 KRAS 突变的 GxM 关联结直肠癌 (CRC) 使用目标 1 中类似的方法。这些研究将应用一个新概念发现癌症结果种族差异的新生物驱动因素（通过突变频率来衡量）。这项研究的结果有可能为机制研究提供信息，而这反过来又会带来新的结果癌症的治疗策略在突变频率和结果方面表现出种族差异。