Genomics of Renal Cancer in Patients of African Ancestry

项目总结 在肾细胞癌(RCC)亚型中，黑人患者的预后比白人患者差。黑色 与白人患者相比，患者的发病率也更高，尤其是在 乳头状亚型。环境和结构因素可能是造成这种差距的原因；然而， 有证据表明，体细胞基因组差异也起到了作用。尽管非洲患者(AFR) 血统在大多数公开数据库中的代表性不足，VHL基因突变减少和 AFR血统的透明细胞肾癌患者的染色体3p缺失与欧洲人(EUR)的比较 血统。在我们的初步数据中，随着样本量的增加，我们发现了NF2突变和染色体22q 在AFR血统患者的RCC中，缺失在不同亚型中更为常见。这些初步调查结果 基因组与祖先的相关性使我们提出假设，生存差异可能是部分原因 由AFR血统患者肿瘤中丰富的分子特征决定。 在这个项目中，我们将采用三种并行的方法来理解肿瘤分子之间的差异 有AFR和EUR血统的患者。在第一个目标中，我们将进行全面的计算分析 更大的RCC数据集，以验证和识别这两名患者之间新的基因组肿瘤差异 人口。在第二个目标中，我们将从功能上表征“特定于祖先的”基因组改变 在初步研究中发现，包括两个非整倍体事件-染色体3p缺失和染色体 22q缺失。最后，在第三个目标中，我们将超越面板和外显子测序来确定新的驱动因素 事件，使用全基因组测序结合对黑人患者肿瘤的RNA测序。这个 这些实验的结果将导致对这位患者肾细胞癌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司机改变不仅可以改善诊断 对AFR血统的肾癌患者进行测试，但也将确定新的治疗靶点以减少差异 在RCC中观察到。

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.