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.

项目概要 在肾细胞癌 (RCC) 黑人亚型中，黑人患者的预后比白人患者差。 与白人患者群体相比，患者的发病率也更高，特别是对于 环境和结构因素可能导致这种差异；但是，确实存在这种差异。 有证据表明，非洲（AFR）患者的体细胞基因组差异也有影响。 在大多数公开数据库中，血统代表性不足，VHL 基因突变减少， 与欧洲 (EUR) 相比，AFR 血统的透明细胞肾细胞癌患者中观察到染色体 3p 缺失 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。 这些初步发现在 AFR 血统患者的 RCC 中更常见。 基因组与祖先的相关性使我们认识到生存差异可能是部分解释的 AFR 血统患者肿瘤中富含的分子特征。 在这个项目中，我们将采取三种并行的方法来理解之间的分子肿瘤差异 在第一个目标中，我们将对 AFR 和 EUR 血统的患者进行全面的计算分析。 更大的 RCC 数据集来验证和识别这两名患者之间新的基因组肿瘤差异 在第二个目标中，我们将从功能上表征“祖先特异性”基因组改变。 初步研究中发现，包括两个非整倍体事件——染色体3p缺失和染色体 最后，在第三个目标中，我们将超越面板和外显子组测序来识别新的驱动程序。 对黑人患者的肿瘤进行全基因组测序和 RNA 测序。 这些实验的结果将带来关于该患者肾细胞癌特定生物学的新见解 我们的研究将揭示与血统相关的驾驶员改变，这不仅可以改善诊断。 对 AFR 血统的 RCC 患者进行测试，但还将确定新的治疗靶点以减少差异 在 RCC 中观察到。