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，并且长期以来已知非裔美国男性与其他种族群体的男性相比表现出更高的发病率和增加的死亡率。虽然社会经济因素和获得医疗保健的机会不平等无疑是造成这种差异的原因，但在调整这些因素后，发病率和结局的差异仍然存在。因此，肿瘤生物学和/或遗传学方面可能是非洲裔美国人前列腺癌不良结局的基础。然而，到目前为止，很少有研究深入探讨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因素的理解仍然不完整。该提案的主要目标是对非裔美国人前列腺癌进行明确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并行测序平台，以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定的染色体重排）的谱。我们将利用这个平台，利用目前在布罗德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，在从非洲裔美国男性获得的200个前列腺肿瘤标本的队列中进行肿瘤突变分析。将在该队列中观察到的体细胞改变模式与欧美前列腺癌的体细胞改变模式进行比较。此外，我们将测试受复发性改变的前列腺癌基因组位点影响的顶级候选基因对欧洲或非洲血统男性获得的原代前列腺上皮细胞中致瘤表型的影响。一旦完成，该项目应提供决定性的见解，在非洲裔美国人前列腺癌的体细胞遗传改变的频谱和功能相关性，从而肯定或反驳的假设，这些生物因素巩固这种普遍的癌症健康差距。 公共卫生相关性：与欧洲裔美国人相比，非洲裔美国人男性的前列腺癌发生频率更高，发病年龄更早，死亡率更高。毫无疑问，这种深刻差异的成因是多因素的;然而，以前没有对非洲裔美国人前列腺癌的遗传学和生物学进行过详细的研究。这项资助的重点是使用靶向大规模平行测序对非洲裔美国人前列腺癌中复发性体细胞遗传改变进行系统研究。此外，我们将查询来自非洲裔美国人和欧洲裔美国人患者的细胞培养模型中的特定癌症改变。完成后，这项研究可能会成为非洲裔美国人前列腺癌中最全面的功能遗传学研究之一。这项研究的见解可能会为新的治疗策略提供信息，这些策略在不同的人群中广泛相关。

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. PUBLIC HEALTH RELEVANCE: Prostate cancer in African-American men occurs more frequently, earlier in life, and with increased lethality when compared to European Americans. Undoubtedly, the genesis of this profound disparity is multi-factorial; however, a detailed study of the genetics and biology of African-American prostate cancer has not previously been undertaken. The focus of this grant is a systematic study of recurrent somatic genetic alterations in African-American prostate cancer using targeted, massively parallel sequencing. In addition, we will query specific cancer alterations in cell culture models derived from African-American and European-American patients. Upon completion, this study will likely constitute one of the most comprehensive functional genetic efforts yet undertaken in African-American prostate cancer. Insights from this study may inform new treatment strategies that prove broadly relevant across diverse human populations.