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: 10251031
• 负责人: Ganesh S Palapattu
• 金额: $ 34.48万
• 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/10251031
• 关键词: American; Bioinformatics; Biological Assay; Biometry; Body mass index; 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; brca gene; cancer genetics; clinical Diagnosis; clinically significant; cohort; detection assay; follow-up; genetic risk factor; improved; innovation; men; multimodality; next generation sequencing; novel; overtreatment; performance tests; prospective; prospective test; prostate biopsy; prostate cancer risk; risk stratification; 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.

密歇根州前列腺孢子的项目2旨在改善对不利风险前列腺的早期发现 癌症（PCA）通过采用一种新型的基于尿液的下一代测序（NGS）测定法。最近的研究 已经证明具有某些种系遗传改变的男性（例如BRCA 1/2和Lynch综合征） 可能会增加可能具有侵略性PCA的风险。处于遗传风险增加的男性代表了新的 公认的小组，早期发现特别引人注目。一般来说，这是一个中心问题 PCA筛查固有的是Gleason 6（低风险）疾病的严重过度诊断。平衡 Gleason 6 PCA的过度治疗已引入了许多主动监视（AS）策略。 过渡到确定治疗（例如，手术或辐射）可以通过风险重新分类的证据触发 通常是由于成绩的进展。改善了以前男性的早期检测 被诊断为Gleason 6 PCA AS代表了改善和优化资源利用的主要机会 （前列腺活检和MRI）以及临床意义的PCA的诊断。如何可靠的身份证明 潜在的积极性PCA，因此可以适当推荐治疗继续代表关键 知识差距。基于成功的孢子项目的先前工作，涉及MI前列腺分数 （MIPS）测试（使用转录介导的尿液KLK3，PCA3和 tmprss2：erg），我们开发了一种新型的基于尿液的NGS分析（MIPS-NGS）来检测不利的风险 （≥GLEASON7）PCA。 MIPS-NGS是一个靶向的RNA-SEQ分析，完成了83个前列腺，PCA和侵略性 PCA特异性转录本（例如LNCRNA，ETS基因融合，HOXB13）。我们假设MIPS-NG可以 改善对PCA不利风险的早期检测，并将通过以下特定目的进行测试： 目标1：评估MIPS-NGs作为具有高遗传风险的男性的PCA早期检测试验的效用。 目标2：确定MIPS-NG是否可以预测男性的成绩。 Sub-aim 2.1：测试 仅MIPS-NG仅用于早期检测到两个前瞻性队列中的年级进展。 sub-aim 2.2：to 开发基于MIPS-NGS的多维临床工具，以优化对年级进展的早期检测 在AS的男人中。 成功完成该项目后，我们将为我们的创新尿液NGS分析确定角色 在早期发现不利的风险PCA在两个重要情况下：1）处于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，生物信息学专家组成， 生物统计学和癌症遗传学，再加上我们独特的机构资源（密歇根州泌尿外科手术） 改善合作（音乐），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/弗雷德·哈钦森癌症研究 中心和国家癌症研究所）被中毒以执行我们既定的研究计划。