Genomics and Predictive Modeling of Prostate Cancer Heath Disparity

描述(申请人提供)：非裔美国人(AA)男性前列腺癌的发病率和发病年龄较早，疾病死亡率是高加索美国人(CA)男性的两倍，这与社会经济地位无关。PI实验室最近的工作揭示了CA和AA男性转移性前列腺癌和原发前列腺癌的基因组组织，并证明了先天肿瘤特征可能是观察到的健康差异的原因。与正常的、非癌症的基因组相比，肿瘤基因组包含介导启动和进展的基因的拷贝数改变(CNA)的获得或丢失。当年龄、Gleason评分和分期相匹配时，与CA前列腺癌的基因组相比，原发性AA前列腺癌的基因组中更多的CNA易于转移。这项研究将通过体细胞基因组DNA拷贝数分析来验证最初的前列腺癌转移潜力/健康差异研究。将为每个CNA制定风险衡量标准，并将其纳入估计肿瘤转移可能性的模型中。遗传预测指标将与临床风险预测指标相结合，开发和评估一个全面的统计风险评估模型。将评估接收器-操作员曲线下的区域，以测量和比较判别准确度。将进行配对分析，以证明活检和相应的根治性前列腺切除术肿瘤标本中存在类似的CNA特征。此外，全基因组测序将应用于不同特征的AA和CA肿瘤-不同转移潜力和转移的原发肿瘤。将对这些突变、重复和缺失进行分析，这些突变、重复和缺失可能具有因果作用。

DESCRIPTION (provided by applicant): African American (AA) men have an increased incidence and earlier age of onset of prostate cancer and two-fold higher rate of mortality from disease than Caucasian American (CA) men that does not correlate with socioeconomic status. Recent work in the PI's laboratory has shed light on the organization of the genomes of metastatic prostate cancers and primary prostate cancers from CA and AA men and has demonstrated that innate tumor characteristics may contribute to the observed health disparities. Compared to normal, non-cancerous genomes, the tumor genomes contain copy number alteration (CNA) gains or losses of genes that mediate initiation and progression. When matched for age, Gleason score and stage, the genomes of primary AA prostate cancers have a greater number of CNAs that predispose to metastasis compared to the genomes of CA prostate cancers. This study will validate the initial prostate cancer metastatic potential/health disparity study through somatic genomic DNA copy number analysis. A risk metric will be developed for each CNA that will be incorporated into a model that estimates the likelihood that a tumor will metastasize. The genetic predictors will be combined with clinical risk predictors to develop and evaluate a comprehensive statistical risk assessment model. Areas under the receiver-operator curves will be assessed to measure and compare the discriminatory accuracy. Paired analyses will be performed to demonstrate the presence of similar CNA profiles in biopsy and corresponding radical prostatectomy tumor specimens. In addition, whole genome sequencing will be applied to AA and CA tumors of different characteristics - primaries of different metastatic potential and metastases. These will be analyzed for mutations, duplications, and deletions that may have had a causal role.