Project 3: Integrative and Functional Genomics of Aggressive Prostate Cancer in African American Men

摘要-项目3 长期以来，人们一直知道，非洲裔美国人的发病率和死亡率较高， 前列腺癌与其他种族的男性相比。社会经济因素和获得保健服务的机会不平等 护理无疑会导致这种差异;然而， 考虑到这些因素。这就提出了肿瘤生物学和/或遗传改变的差异 也有助于与非洲裔美国人前列腺癌相关的不良后果。的总体目标 本项目旨在全面研究突变景观和致癌基因表达模式， 存在于原发性非洲裔美国人前列腺癌中。为此，我们将描述约3,000个肿瘤 使用全外显子组测序和靶向测序对来自RESPOND队列的样本进行测序。约 其中1,000个肿瘤也将接受转录组分析。这些数据将用于研究 前列腺癌遗传学和肿瘤侵袭性之间的关系，并将与前列腺癌的男性队列进行比较。 欧洲血统，以确定是否有任何遗传或转录改变显示差异患病率 作为祖先的功能。此外，我们将使用原代前列腺上皮细胞的体外研究来测试是否 常见的前列腺癌改变在引入非恶性肿瘤时发挥更强大的致瘤作用， 来自非裔美国人的前列腺细胞与来自白色人的前列腺上皮细胞的比较。这个项目 应该能够明确了解非裔美国人前列腺的体细胞遗传学改变特征， 癌症及其在推动侵袭性疾病和不良后果中可能发挥的作用， 可能是其他祖先群体。

Abstract – Project 3 It has long been known that African American men experience a higher incidence and increased mortality from prostate cancer compared to men of other ethnic groups. Socio-economic factors and unequal access to health care undoubtedly contribute to this disparity; however, differences in incidence and outcome remain after considering these factors. This raises the possibility that differences in tumor biology and/or genetic alterations also contribute to the adverse outcomes linked to African American prostate cancer. The over-arching goal of this Project is to comprehensively interrogate the mutational landscape and oncogenic gene expression patterns present in primary African American prostate cancer. Towards this end, we will characterize ~3,000 tumor samples from the RESPOND cohort using whole-exome sequencing and targeted sequencing. Approximately 1,000 of these tumors will also undergo transcriptome analysis. This data will be used to study the relationship between prostate cancer genetics and tumor aggressiveness, and will be compared to cohorts of men of European descent to determine whether any genetic or transcriptional alterations show differential prevalence as a function of ancestry. In addition, we will use in vitro studies of primary prostate epithelial cells to test whether common prostate cancer alterations exert more robust tumorigenic effects when introduced into non-malignant prostate cells from African American men compared to prostate epithelial cells from white men. This project should enable definitive insights into the somatic genetic alterations characteristic of African American prostate cancer and the role(s) they might play in driving aggressive disease and adverse outcomes within this and potentially other ancestral groups.