Noninvasive Risk Stratification of Prostate Cancer Using Cell-Free Nucleic Acids

项目概要/摘要 每年，美国有超过161，000名男性被诊断患有前列腺癌。虽然前列腺 癌症仍然是癌症相关死亡率的重要原因，早期筛查工作受到以下因素的阻碍： 事实上，大多数病例并不是立即致命的，积极的治疗或重新活检， 不良副作用该提案的目标是开创新的非侵入性诊断，以区分 高风险与低风险前列腺癌之间的差异，以指导临床管理。 这一提议的核心假设是，拷贝数变异和甲基化标志物可以被 作为侵入性组织标志物的替代物，在循环核酸中非侵入性地发现， 标记物可使局部前列腺癌分层。第一个目标将评估两个非侵入性 使用基于下一代测序（NGS）的方法来检测前列腺癌的生物标志物。血浆 将检测尿液样本的拷贝数变异和甲基化标志物， 与前列腺手术中并发的前列腺癌组织进行对比。第二个目标是评估 第一种非侵入性方法的目的是能够对局部前列腺癌进行风险分层， 横断面研究。 在K 08指导临床科学家研究职业发展奖申请中， 申请人顾伟，医学博士，博士，是加州大学旧金山分校实验室系的委员会认证的临床病理学家 药这项建议包括一个五年计划，以提高他的研究和专业技能 目标是成为一名独立的医生-科学家，专注于推进非侵入性 使用无细胞核酸作为癌症生物标志物进行检测。 职业发展计划的基本组成部分是：（1）来自多学科团队的指导 在先进分子技术，生物信息学， 生物统计学和临床研究设计;（2）正式教学法，以扩展临床研究知识 设计，癌症生物学，生物信息学和专业发展;（3）实验室测试和 分析游离DNA作为前列腺癌的生物标志物;（4）专业发展 过渡到独立，以及（5）R 01应用程序的数据收集。导师制， 已成立了一个多学科科学委员会，以促进该提案的目标， 走向独立。这项计划将在加州大学旧金山分校实施 弗朗西斯科，它提供了一个特殊的研究环境，国家的最先进的设施，和支持 科学界，这将是一个理想的环境，促进职业发展和项目 成功

PROJECT SUMMARY/ABSTRACT Every year, more than 161,000 men in the U.S. are diagnosed with prostate cancer. While prostate cancer remains a significant cause of cancer related mortality, early screening efforts are hampered by the fact that the majority of cases are not imminently deadly and active treatments or re-biopsies have adverse side effects. The goal of this proposal is to pioneer new non-invasive diagnostics to distinguish between high-risk versus low-risk prostate cancers in order to guide clinical management. The core hypothesis of this proposal is that copy number variations and methylation markers can be found non-invasively in circulating nucleic acids as a surrogate for invasive tissue markers, and these markers can risk stratify localized prostate cancers. The first aim will evaluate two non-invasive biomarkers for prostate cancer using next-generation sequencing (NGS)-based approaches. Plasma and urine samples will be tested for copy number variations and methylation markers, and compared against concurrent prostate cancer tissue taken from prostate surgery. The second aim will evaluate the non-invasive approaches in the first aim for the ability to risk stratify localized prostate cancer in a cross-sectional study. In this K08 Mentored Clinical Scientist Research Career Development Award application, the applicant, Wei Gu, MD, PhD, is a board certified Clinical Pathologist at UCSF Department of Laboratory Medicine. This proposal encompasses a five-year plan to enhance his research and professional skills with the goal of becoming an independent physician-scientist focused on advancing non-invasive testing using cell-free nucleic acids as cancer biomarkers. Essential components of the career development plan are: (1) mentorship from a multidisciplinary team of scientists and physician-scientists with expertise in advanced molecular techniques, bioinformatics, biostatistics, and clinical study design; (2) formal didactics to expand on knowledge in clinical study design, cancer biology, bioinformatics, and professional development; (3) laboratory testing and analysis of cell-free DNA as biomarkers for prostate cancer; (4) professional development in the transition to independence, and (5) data collection for an R01 application. A mentorship and multidisciplinary scientific committee has been assembled to facilitate the proposal aims and progression towards independence. This plan will be implemented at University of California, San Francisco, which provides an exceptional research environment, state-of-art facilities, and a supportive scientific community that will be an ideal environment to foster career development and project success.