Genomics and Predictive Modeling of Prostate Cancer Heath Disparity

前列腺癌健康差异的基因组学和预测模型

• 批准号: 8899457
• 负责人: Harry Ostrer
• 金额: $ 31.54万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8899457
• 关键词: African American; Age; Age of Onset; Area; Biopsy; Characteristics; DNA copy number; Disease; Ethnic group; Genes; Genome; Genomic DNA; Genomics; Gleason Grade for Prostate Cancer; Incidence; Laboratories; Light; Malignant neoplasm of prostate; Measures; Mediating; Metastatic Prostate Cancer; Modeling; Mutation; Natural Selections; Neoplasm Metastasis; Outcome; Patient observation; Primary Neoplasm; Principal Investigator; Radical Prostatectomy; Research; Risk; Risk Assessment; Role; Socioeconomic Status; Specimen; Staging; Translating; Tumor Biology; Work; cancer genome; caucasian American; clinical risk; cohort; genetic predictors; genome sequencing; health disparity; men; mortality; novel; predictive modeling; theories; tumor

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.

描述（由申请人提供）：非裔美国人（AA）男性前列腺癌的发病率增加，发病年龄较早，疾病死亡率是白人美国人（CA）男性的两倍，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性前列腺癌基因组的组织，并证明先天肿瘤特征可能导致观察到的健康差异。与正常的非癌基因组相比，肿瘤基因组包含介导起始和进展的基因的拷贝数改变（CNA）获得或丢失。当年龄、Gleason评分和分期匹配时，与CA前列腺癌的基因组相比，原发性AA前列腺癌的基因组具有更大数量的易发生转移的CNA。本研究将通过体细胞基因组DNA拷贝数分析验证初始前列腺癌转移潜力/健康差异研究。将为每个CNA开发一个风险指标，该指标将被纳入估计肿瘤转移可能性的模型中。遗传预测因子将与临床风险预测因子相结合，以开发和评估综合统计风险评估模型。将评估受试者-操作者曲线下面积，以测量和比较区分准确度。将进行配对分析，以证明活检和相应根治性乳腺癌切除术肿瘤标本中存在相似的CNA谱。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。将分析这些可能具有因果作用的突变、重复和缺失。

项目成果

Clustering-Based Method for Developing a Genomic Copy Number Alteration Signature for Predicting the Metastatic Potential of Prostate Cancer.

基于聚类的方法开发基因组拷贝数改变特征以预测前列腺癌的转移潜力。

• DOI: 10.1155/2012/873570
• 发表时间: 2012
• 期刊: Journal of probability and statistics
• 影响因子: 1.1
• 作者: Pearlman,Alexander;Campbell,Christopher;Brooks,Eric;Genshaft,Alex;Shajahan,Shahin;Ittman,Michael;Bova,GSteven;Melamed,Jonathan;Holcomb,Ilona;Schneider,RobertJ;Ostrer,Harry
• 通讯作者: Ostrer,Harry