Project 2: Integrating a Novel MiPS-Based Next-Generation Sequencing Urine Assay for the Early Detection of Unfavorable Risk Prostate Cancer

项目 2：集成基于 MiPS 的新型下一代测序尿液检测，以早期检测不利的前列腺癌风险

• 批准号: 10006871
• 负责人: Ganesh S Palapattu
• 金额: $ 41.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-11 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006871
• 关键词: American; Bioinformatics; Biological Assay; Biometry; Clinic; Clinical; Clinical Management; Collaborations; Coupled; DNA Sequence Alteration; Data; Decision Aid; Diagnosis; Disease; Early Diagnosis; Fred Hutchinson Cancer Research Center; Funding; Gene Fusion; Genetic Risk; Genomics; Health; Hereditary Nonpolyposis Colorectal Neoplasms; Institutes; KLK3 gene; Knowledge; Laboratories; Light; Localized Disease; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Medicine; Michigan; Molecular; Monitor; Mutation; National Cancer Institute; Operative Surgical Procedures; Pathologic; Patients; Periodicity; Population; Population Sciences; Prevention; Prospective cohort; Prospective cohort study; Prostate; Radiation; Reflex action; Research; Resources; Risk; Role; Sampling; Screening for Prostate Cancer; TMPRSS2 gene; Testing; Transcript; Universities; Urine; Urologic Surgical Procedures; Washington; Work; advanced prostate cancer; base; cancer genetics; clinical Diagnosis; clinically significant; cohort; follow-up; genetic risk factor; improved; innovation; men; multimodality; next generation sequencing; novel; overtreatment; performance tests; prospective; prospective test; prostate biopsy; prostate cancer risk; serum PSA; surveillance strategy; surveillance study; tool; transcription mediated amplification; transcriptome sequencing; transcriptomics

Project 2 of the Michigan Prostate SPORE seeks to improve the early detection of unfavorable risk prostate cancer (PCa) by employing a novel urine-based next-generation sequencing (NGS) assay. Recent studies have demonstrated that men with certain germline genetic alterations (e.g., BRCA 1/2 and Lynch syndrome) may be at increased risk of potentially aggressive PCa. Men at increased genetic risk represent a newly recognized group in whom early detection is particularly compelling. Generally speaking, a central problem inherent to PCa screening is the profound overdiagnosis of Gleason 6 (low risk) disease. To counterbalance the overtreatment of Gleason 6 PCa, a number of active surveillance (AS) strategies have been introduced. Transition to definitive treatment (e.g., surgery or radiation) can be triggered by evidence of risk reclassification often due to grade progression. Improved early detection of grade progression in men with previously diagnosed Gleason 6 PCa on AS represents a major opportunity to improve and optimize resource utilization (prostate biopsy and MRI) as well as the diagnosis of clinically significant PCa. How to reliably identify potentially aggressive PCa so treatment can be appropriately recommended continues to represent a critical knowledge gap. Building on prior work from a successful SPORE project involving the Mi Prostate Score (MiPS) test (using transcription-mediated amplification quantification of urine KLK3, PCA3, and TMPRSS2:ERG), we have developed a novel urine-based NGS assay (MiPS-NGS) to detect unfavorable risk (≥Gleason 7) PCa. MiPS-NGS is a targeted RNA-seq assay comprised of 83 prostate-, PCa-, and aggressive PCa-specific transcripts (e.g., lncRNAs, ETS genes fusions, HOXB13). We hypothesize that MiPS-NGS can improve the early detection of unfavorable risk PCa and will test this through the following Specific Aims: Aim 1: To assess the utility of MiPS-NGS as a PCa early detection assay in men at high genetic risk. Aim 2: To determine whether MiPS-NGS can predict grade progression in men on AS. Sub-Aim 2.1: To test MiPS-NGS alone for the early detection of grade progression in two prospective AS cohorts. Sub-Aim 2.2: To develop a multi-dimensional clinical tool based on MiPS-NGS to optimize early detection of grade progression in men on AS. Upon successful completion of this project, we will have established a role for our innovative urine NGS assay in the early detection of unfavorable risk PCa in two important contexts: 1) men at high genetic risk and 2) AS. Our interdisciplinary team, comprised of experts in clinical management, genomics, bioinformatics, biostatistics, and cancer genetics, coupled with our unique institutional resources (Michigan Urological Surgery Improvement Collaborative (MUSIC), University of Michigan Prostate Cancer Risk Clinic (PCRC), and the Karmanos Cancer Institute) and collaborations (University of Washington/Fred Hutchinson Cancer Research Center and the National Cancer Institute), is uniquely poised to execute our stated research plan.

密歇根前列腺 SPORE 项目 2 旨在改善前列腺不良风险的早期检测 最近的研究通过采用一种新型的基于尿液的下一代测序（NGS）检测来检测癌症（PCa）。 已证明具有某些种系遗传改变的男性（例如 BRCA 1/2 和林奇综合征） 患有潜在侵袭性前列腺癌的风险可能会增加，遗传风险增加的男性代表了一种新的疾病。 一般而言，这是一个核心问题。 PCa 筛查的本质是对 Gleason 6（低风险）疾病的严重过度诊断。 由于格里森 6 PCa 的过度治疗，许多主动监测（AS）策略被引入。 风险重新分类的证据可以触发向确定性治疗（例如手术或放射）的转变 通常是由于以前有过年级进展的男性的成绩进展得到了改善。 AS 上诊断的 Gleason 6 PCa 代表了改善和优化资源利用率的重大机会 （前列腺活检和 MRI）以及具有临床意义的 PCa 的诊断如何可靠地识别。 潜在的侵袭性前列腺癌，因此可以适当推荐治疗仍然是一个关键 知识差距以涉及 Mi 前列腺评分的成功 SPORE 项目的先前工作为基础。 (MiPS) 测试（使用转录介导的扩增定量尿液 KLK3、PCA3 和 TMPRSS2:ERG)，我们开发了一种新型基于尿液的 NGS 检测 (MiPS-NGS) 来检测不利风险 (≥Gleason 7) MiPS-NGS 是一种靶向 RNA-seq 检测，包含 83 个前列腺、PCa 和侵袭性样本。 PCa 特异性转录本（例如，lncRNA、ETS 基因融合、HOXB13）。 提高对 PCa 不利风险的早期检测，并将通过以下具体目标进行测试： 目标 1：评估 MiPS-NGS 作为 PCa 早期检测方法在高遗传风险男性中的效用。 目标 2：确定 MiPS-NGS 是否可以预测男性 AS 的成绩进展 子目标 2.1：测试。 MiPS-NGS 单独用于早期检测两个前瞻性 AS 队列的分级进展。 开发基于 MiPS-NGS 的多维临床工具，以优化分级进展的早期检测 男性 AS 患者。 该项目成功完成后，我们将在创新的尿液 NGS 检测中发挥作用 在两个重要背景下早期发现 PCa 不利风险：1) 具有高遗传风险的男性和 2) AS。 我们的跨学科团队由临床管理、基因组学、生物信息学、 生物统计学和癌症遗传学，加上我们独特的机构资源（密歇根泌尿外科 改进合作组织 (MUSIC)、密歇根大学前列腺癌风险诊所 (PCRC) 和 Karmanos 癌症研究所）和合作（华盛顿大学/Fred Hutchinson 癌症研究中心） 中心和国家癌症研究所），以独特的方式执行我们规定的研究计划。