Germline Determinants of Prostate Cancer Evolution

前列腺癌进化的种系决定因素

• 批准号: 10587968
• 负责人: Paul Christopher Boutros
• 金额: $ 62.89万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587968
• 关键词: African ancestry; Age; Aggressive behavior; American; Asian ancestry; Asian population; Autopsy; BRCA2 Mutation; Bioinformatics; Biological Markers; Biopsy; Cancer Etiology; Castration; Cessation of life; Clinical; DNA Repair; DNA sequencing; Data; Data Set; Diagnosis; Disease; Disease Resistance; Distant; European ancestry; Evolution; Genes; Genetic; Genetic Polymorphism; Genome; Genomics; Germ-Line Mutation; Heritability; Hispanic Populations; Hispanic ancestry; Incidence; Individual; Indolent; Link; Local Therapy; Malignant Neoplasms; Malignant neoplasm of prostate; Medical Care Costs; Methods; Molecular; Molecular Evolution; Monitor; Morbidity - disease rate; Newly Diagnosed; Odds Ratio; Pathway Analysis; Pathway interactions; Patients; Population; Population Heterogeneity; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Publishing; Rectum; Risk; Sample Size; Serum; Shapes; Site; Skin Cancer; Solid; Somatic Mutation; Stratification; TMPRSS2 gene; Testing; United States; Variant; aging population; biobank; cancer diagnosis; clinical risk; cohort; cost; digital; follow-up; gene repair; lifetime risk; male health; men; novel; polygenic risk score; rectal; repository; risk prediction; risk stratification; serum PSA; standard of care; transcriptome; tumor; tumor diagnosis; whole genome

Abstract Prostate cancer is the most commonly diagnosed non-skin cancer in men, and the second most common cause of cancer death for men. It is a high-incidence, high-fatality, high-morbidity and high-cost cancer that is growing increasingly frequent in our aging population. Clinically, the majority of prostate cancers present as indolent, and are unlikely to significantly influence a man’s health over his lifetime. Nevertheless, a significant number of prostate tumors are diagnosed while localized but have substantial metastatic potential. Once these colonize distant sites, they become almost uniformly lethal. Current standard of care for clinical risk-stratification involves serum abundance of prostate specific antigen (PSA), a digital rectal exam and biopsy. While these are beneficial, ~30-40% of men are over- or under-treated. Therefore, a central problem in prostate cancer remains understanding this dramatic variability in the aggressiveness of localized prostate cancers. We hypothesize that the clinical and molecular evolution of localized prostate cancers are shaped by germline genomic features. Strong preliminary data support this idea. Prostate cancer is the most heritable solid cancer. It shows strong variability across ancestries, and specific genetic features predict both risk of incidence and disease aggression. We will test our hypothesis with three complementary aims. Aim #1 quantifies germline-somatic interactions using transcriptome-wide association studies (TWAS) and pathway-somatic interaction analysis. Aim #2 then identifies ancestry-based germline-somatic interactions. Finally Aim #3 will assess the generalizability of germline-somatic interactions for clinical risk prediction by developing a targeted DNA- sequencing panel and evaluating biomarker potential in large patient cohorts. To achieve these aims, we will leverage publicly available datasets as well as biobanking repositories at UCLA, linked to both established and novel bioinformatics methods. Together, these aims provide three complementary strategies to quantify how the specific clinical and molecular evolutionary features of localized prostate cancer are influenced by specific germline polymorphisms.

摘要 前列腺癌是男性最常见的非皮肤癌，也是第二常见的原因 男性的癌症死亡率。它是一种高发、高病死、高致残和高费用的癌症，且呈增长趋势 在我们的老龄化人口中越来越常见。临床上，大多数前列腺癌表现为惰性， 不太可能在一个人的一生中对他的健康产生重大影响。然而，大量的 前列腺肿瘤在局部化时被诊断，但具有实质性的转移潜力。一旦它们殖民 在遥远的地方，它们几乎都是致命的。目前临床风险分层的标准治疗包括 前列腺特异性抗原（PSA）血清丰度，直肠指检和活检。虽然这些都是有益的， 大约30-40%的男性接受了过度或不足的治疗。因此，前列腺癌的一个中心问题仍然是 了解局限性前列腺癌侵袭性的巨大差异。我们假设 局限性前列腺癌的临床和分子进化是由生殖细胞基因组决定的， 功能.强有力的初步数据支持这一观点。前列腺癌是遗传性最强的实体癌。它显示 不同祖先之间存在很强的变异性，特定的遗传特征可以预测发病率和疾病的风险 侵略我们将用三个互补的目标来检验我们的假设。目标#1量化生殖细胞-体细胞 使用全转录组关联研究（TWAS）和途径-体细胞相互作用分析进行相互作用。 目标#2然后确定基于祖先的生殖系-体细胞相互作用。最后，目标#3将评估 通过开发一种靶向的DNA， 测序面板和评估生物标志物的潜力，在大型患者队列。为达致这些目标，我们会 利用公开可用的数据集以及加州大学洛杉矶分校的生物库存储库，与已建立的 新的生物信息学方法。总之，这些目标提供了三个互补的战略，以量化 局限性前列腺癌的特定临床和分子进化特征受特定 生殖系多态性