Systematic Genetic Characterization of African American Prostate Cancer

描述（由申请人提供）：在美国，前列腺癌是癌症相关死亡的第二大原因，非洲裔美国男性长期以来一直被认为比其他种族的男性表现出更高的发病率和死亡率。虽然社会经济因素和获得医疗保健的机会不平等无疑造成了这种差异，但在调整这些因素后，发病率和结果的差异仍然存在。因此，肿瘤生物学和/或遗传学方面可能是非裔美国人前列腺癌不良结局的基础。然而，迄今为止，很少有研究深入询问非裔美国人前列腺癌的分子生物学或体细胞遗传学，这意味着我们对影响这些差异的各种因素的理解仍然不完整。这项建议的首要目标是进行一个明确的非裔美国人前列腺癌的体细胞遗传和功能表征。为了实现这一目标，我们将开发一个有针对性的大规模平行测序平台，询问与前列腺癌相关的复发性改变（碱基突变、染色体拷贝数变化和选择性染色体重排）的频谱。我们将利用这个平台对来自非裔美国男性的200个前列腺肿瘤标本进行肿瘤突变分析，利用Broad研究所和其他地方正在进行的前列腺癌基因组测序研究的知识。在这个队列中观察到的体细胞改变模式将与欧美前列腺癌的模式进行比较。此外，我们将测试受反复改变的前列腺癌基因组位点影响的顶级候选基因对来自欧洲或非洲裔男性的原发性前列腺上皮细胞的致瘤表型的影响。一旦完成，该项目将为非裔美国人前列腺癌体细胞遗传改变的范围和功能相关性提供决定性的见解，从而肯定或反驳这些生物因素支撑这种普遍存在的癌症健康差异的假设。

DESCRIPTION (provided by applicant): In the United Sates, prostate cancer is the second leading cause of cancer-related deaths, and African- American men have long been known to exhibit a higher incidence and increased mortality compared to men of other ethnic groups. Although socioeconomic factors and unequal access to health care undoubtedly contribute to this disparity, differences in incidence and outcome persist after adjusting for these factors. Thus, tumor biological and/or genetic aspects may underpin adverse outcomes in African-American prostate cancer. To date, however, few studies have queried the molecular biology or somatic genetics of African-American prostate cancer in-depth, meaning that our understanding of the spectrum of factors influencing these disparities remains incomplete. The over-arching goal of this proposal is to undertake a definitive somatic genetic and functional characterization of African-American prostate cancer. To accomplish this goal, we will develop a targeted, massively parallel sequencing platform that interrogates the spectrum of recurrent alterations (base mutations, chromosomal copy number changes, and selected chromosomal rearrangements) relevant to prostate cancer. We will utilize this platform to perform tumor mutation profiling in a cohort of two hundred prostate tumor specimens obtained from African American men, leveraging knowledge from prostate cancer genome sequencing studies currently ongoing at the Broad Institute and elsewhere. Patterns of somatic alterations observed in this cohort will be compared to those of European-American prostate cancer. In addition, we will test top candidate genes affected by recurrently altered prostate cancer genomic loci for effects on the tumorigenic phenotype in primary prostate epithelial cells obtained from men of European or African descent. Once completed, this project should provide decisive insights into the spectrum of and functional relevance of somatic genetic alterations in African-American prostate cancer, thereby affirming or refuting the hypothesis that these biological factors undergird this pervasive cancer health disparity.