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

密歇根州前列腺癌孢子项目2寻求改善对不良风险前列腺癌的早期检测 通过使用一种新的基于尿液的下一代测序(NGS)分析来检测癌症(PCA)。最新研究 已证明具有某些生殖系基因改变的男性(例如BRCA1/2和林奇综合征) 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着一种新的 公认的群体，他们的早期发现特别令人信服。总的来说，一个中心问题是 PCa筛查固有的是对格里森6(低风险)病的严重过度诊断。制衡 对于格里森6前列腺癌的过度治疗，已经引入了一些主动监测(AS)策略。 风险重新分类的证据可能会触发向最终治疗(例如手术或放射治疗)的过渡 通常是由于年级的提高。改善有既往病史的男性的早期分级检测 在AS上诊断出Gleason 6 PCA是提高和优化资源利用率的重大机遇 (前列腺活检和MRI)以及临床上有意义的前列腺癌的诊断。如何可靠地识别 潜在的侵袭性PCa因此可以适当地推荐治疗仍然是一个关键的 知识鸿沟。建立在一个成功的孢子项目的基础上，该项目涉及米氏前列腺评分 (MIPS)试验(使用转录介导的扩增定量测定尿KLK3、PCA3和 TMPRSS2：ERG)，我们开发了一种新的基于尿液的NGS检测方法(MIPS-NGS)来检测不良风险 (≥Gleason 7)Pca。MIPS-NGS是一种靶向rna-seq分析，由83例前列腺癌、前列腺癌和侵袭性 PCA特异性转录本(例如，lncRNAs、ETS基因融合、HOXB13)。我们假设MIPS-NGS可以 改进不良风险主成分分析的早期发现，并将通过以下具体目标进行测试： 目的1：评价MIPS-NGS在高遗传风险男性前列腺癌早期检测中的应用价值。 目的2：确定MIPS-NGS量表能否预测男性强直性脊柱炎的分级进展。子目标2.1：测试 MIPS-NGS单独用于早期检测两个前瞻性队列中的分级进展。次级目标2.2：至 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 在男性的AS上。 在这个项目成功完成后，我们将为我们创新的尿液NGS分析建立一个角色 在早期发现不良风险时，在两个重要的背景下进行主成分分析：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，再加上我们独特的机构资源(密歇根泌尿外科 改善合作(MUSIC)、密歇根大学前列腺癌风险诊所(PCRC)和 卡马诺斯癌症研究所)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)，是唯一准备执行我们声明的研究计划。

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.