Germline Determinants of Prostate Cancer Evolution

前列腺癌进化的种系决定因素

基本信息

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
项目类别：
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

项目摘要

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.

抽象的前列腺癌是男性最常见的非皮肤癌，也是第二常见原因男性癌症死亡。这是一种高度的，高毒气，高多个和高成本的癌症，正在增长在我们老龄化的人口中，越来越多。在临床上，大多数前列腺癌表现为懒惰，不太可能在一生中显着影响男人的健康。然而，大量前列腺肿瘤被诊断出局部，但具有巨大的转移潜力。一旦这些殖民遥远的地点，它们几乎变得均匀致死。当前的临床风险分层护理标准涉及前列腺特异性抗原（PSA），数字直肠检查和活检的血清丰度。虽然这些是有益的，但〜30-40％的男性经过过度治疗。因此，前列腺癌的中心问题仍然存在了解局部前列腺侵略性的这种巨大变化。我们假设局部前列腺癌的临床和分子进化是由种系基因组制成的特征。强大的初步数据支持这一想法。前列腺癌是最遗传的固体癌症。它显示祖先之间的强大差异以及特定的遗传特征可以预测事件和疾病的风险 AIM＃1量化种系及使用整个转录组关联研究（TWA）和途径 - 互动分析的相互作用。 AIM＃2然后确定基于祖先的种系互动。最后，目标＃3将评估种系 - 及其对临床风险预测的种系相互作用的普遍性，通过开发靶向DNA- 测序面板并评估大型患者队列中的生物标志物潜力。为了实现这些目标，我们将利用UCLA的公开可用数据集以及与建立和新型生物信息学方法。这些目标共同提供了三种完整的策略，以量化局部前列腺癌的特定临床和分子进化特征受特定的影响种系多态性。