Genomics of Renal Cancer in Patients of African Ancestry

非洲血统患者肾癌的基因组学

• 批准号: 10648882
• 负责人: Alison M. Taylor
• 金额: $ 26.33万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-02 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648882
• 关键词: 22q; African; African ancestry; Aneuploidy; Biological; Biological Factors; Biology; Black race; Carrots - dietary; Cell Line; Chromosomes; Clear Cell; Clear cell renal cell carcinoma; Clinical; Collaborations; Computer Analysis; Coupled; DNA Sequence Alteration; Data; Data Set; Diagnostic tests; Disease; Disparity; Early Diagnosis; Environmental Risk Factor; European; European ancestry; Event; Foundations; Genes; Genetic; Genome engineering; Genomics; Incidence; Knowledge; Medicine; Modeling; Molecular; Mutate; Mutation; Neurofibromin 2; Oncogenes; Oncogenic; Outcome; Papillary; Patients; Phenotype; Population; Prognostic Marker; Renal Cell Carcinoma; Renal carcinoma; Reporting; Research; Sample Size; Sampling; Socioeconomic Status; Tumor Suppressor Genes; VHL gene; VHL mutation; Variant; black patient; chromosome mutation; cohort; disparity reduction; exome sequencing; experimental study; functional genomics; genome sequencing; genomic data; health disparity; improved; insight; kidney cell; new therapeutic target; novel; novel therapeutics; patient population; precision medicine; public database; racial disparity; racial population; structural determinants; survival disparity; therapeutic target; transcriptome sequencing; tumor; tumorigenesis; whole genome

PROJECT SUMMARY The outcomes of Black patients are worse than white patients across renal cell carcinoma (RCC) subtypes. Black patients also suffer higher disease incidence compared to the white patient population, particularly for the papillary subtype. Environmental and structural factors likely contribute to this disparity; however, there is evidence suggesting that somatic genomic differences also contribute. Although patients of African (AFR) ancestry are under-represented in most publicly available databases, decreased VHL gene mutation and chromosome 3p deletion in clear cell RCC patients of AFR ancestry was observed compared to European (EUR) ancestry. In our preliminary data with increased sample size, we found NF2 mutations and chromosome 22q deletion to be more frequent in RCCs from patients of AFR ancestry across subtypes. These preliminary findings of genomic correlations with ancestry lead us to hypothesize that the survival disparity may be partially explained by molecular features enriched in tumors from patients of AFR ancestry. In this project, we will take three parallel approaches to understanding the molecular tumor differences between patients of AFR and EUR ancestry. In the first aim, we will perform a comprehensive computational analysis of larger RCC datasets to validate and identify new genomic tumor differences between these two patient populations. In the second aim, we will functionally characterize the “ancestry-specific” genomic alterations identified in preliminary studies, including two aneuploidy events - chromosome 3p deletion and chromosome 22q deletion. Lastly, in the third aim, we will move beyond panel and exome sequencing to identify new driver events, using whole-genome sequencing coupled with RNA-sequencing on tumors from Black patients. The results from these experiments will lead to new insights about the specific biology of RCC in this patient population. Our studies will reveal ancestry-associated driver alterations that could not only improve diagnostic testing for RCC patients of AFR ancestry, but will also identify new therapeutic targets to decrease the disparities observed in RCC.

项目摘要 在肾细胞癌（RCC）亚型中，黑人患者的结果比白人患者差。黑色的 与白人患者相比，患者的疾病事件也更高，特别是 乳头亚型。环境和结构性因素可能导致这种差异；但是，有 证据表明体细胞基因组差异也有助于。尽管非洲患者（AFR） 祖先在大多数公开数据库中的代表性不足，VHL基因突变和 与欧洲（欧洲）相比，观察到透明细胞RCC患者的3P染色体缺失（欧洲） 祖先。在样本量增加的初步数据中，我们发现了NF2突变和染色体22q 从亚型的AFR祖先患者的RCC中，删除频率更高。这些初步发现 与祖先的基因组相关性使我们假设可以部分解释生存差异 通过分子特征，富含来自AFR祖先患者的肿瘤。 在这个项目中，我们将采用三种平行的方法来理解分子肿瘤之间的差异 AFR和欧洲血统的患者。在第一个目标中，我们将对 较大的RCC数据集，以验证和确定这两名患者之间的新基因组肿瘤差异 人群。在第二个目标中，我们将在功能上表征“祖先特定”的基因组改变 在初步研究中确定的，包括两个非整倍性事件 - 染色体3p缺失和染色体 22Q删除。最后，在第三个目标中，我们将超越面板和外显子组测序以识别新驱动程序 事件，使用全基因组测序以及对黑人患者肿瘤的RNA测序结合。这 这些实验的结果将导致有关该患者RCC特定生物学的新见解 人口。我们的研究将揭示与祖先相关的驾驶员的改变，不仅可以改善诊断 测试AFR血统患者的RCC患者，但还将确定新的治疗靶点以减少分布 在RCC中观察到。