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

密歇根州前列腺SPORE的项目2旨在改善不利风险前列腺的早期检测 癌症（PCa）的检测，采用新的尿为基础的下一代测序（NGS）测定。最近的研究 已经证明具有某些生殖系遗传改变的男性（例如，BRCA 1/2和Lynch综合征） 可能会增加潜在侵袭性前列腺癌的风险。遗传风险增加的男性代表了一种新的 早期发现特别引人注目的公认群体。一般来说，一个核心问题 PCa筛查固有的是对Gleason 6（低风险）疾病的严重过度诊断。制衡 针对Gleason 6 PCa的过度治疗，已经引入了许多主动监测（AS）策略。 过渡到确定性治疗（例如，手术或放疗）可由风险重新分类的证据触发 往往是因为等级的提升。改善了先前患有糖尿病的男性的年级进展的早期检测 诊断为格里森6型前列腺癌的AS代表了改善和优化资源利用的重要机会 （前列腺活检和MRI）以及临床上显著的PCa的诊断。如何可靠识别 潜在的侵袭性PCa，因此可以适当推荐治疗，这仍然是一个关键的 知识差距。基于先前成功的SPORE项目（涉及Mi前列腺评分）的工作 （MiPS）测试（使用尿KLK 3、PCA 3和KLK 3的转录介导的扩增定量）。 TMPRSS 2：ERG），我们开发了一种新的基于尿的NGS测定（MiPS-NGS）来检测不利的风险 （≥Gleason 7）PCa。MiPS-NGS是一种靶向RNA-seq测定法，由83种前列腺-、PCa-和侵袭性 PCA特异性转录物（例如，lncRNA，ETS基因融合，HOXB 13）。我们假设MiPS-NGS可以 改善不利风险PCa的早期检测，并将通过以下具体目标进行测试： 目的1：评估MiPS-NGS作为高遗传风险男性PCa早期检测试剂盒的实用性。 目的2：确定MiPS-NGS是否可以预测男性AS的等级进展。次级目标2.1：测试 在两个前瞻性AS队列中，单独使用MiPS-NGS用于早期检测分级进展。次级目标2.2： 开发基于MiPS-NGS的多维临床工具，以优化年级进展的早期检测 在男人身上。 在成功完成这个项目后，我们将为我们的创新尿液NGS检测奠定基础。 在两种重要情况下早期检测不利风险PCa：1）高遗传风险男性和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，再加上我们独特的机构资源（密歇根泌尿外科 改善协作（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/Fred哈钦森癌症研究所 中心和国家癌症研究所），是唯一准备执行我们的研究计划。

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.