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

项目摘要/摘要 在美国，每年有超过16.1万名男性被诊断出患有前列腺癌。而前列腺癌 癌症仍然是癌症相关死亡的重要原因，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，而且积极的治疗或再次活检具有 不良副作用。这项提议的目标是开创新的非侵入性诊断方法，以区分 高危前列腺癌与低危前列腺癌之间的关系，以指导临床治疗。 这一建议的核心假设是拷贝数变异和甲基化标记可以是 在循环核酸中非侵入性地发现，作为侵袭性组织标记物的替代品，这些 标志物可能会对局限性前列腺癌进行风险分层。第一个目标将评估两个非侵入性 使用基于下一代测序(NGS)方法的前列腺癌生物标记物。电浆 尿样将被检测拷贝数变异和甲基化标记，并进行比较 从前列腺癌手术中取出的前列腺癌组织。第二个目标是评估 非侵入性方法的第一个目标是能够对局限性前列腺癌进行风险分层。 横断面研究。 在K08指导临床科学家研究职业发展奖的申请中， 申请人顾伟，医学博士，加州大学旧金山分校化验学系临床病理学家。 医学。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内科科学家，专注于推进非侵入性 使用无细胞核酸作为癌症生物标记物的测试。 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 科学家和内科科学家在先进的分子技术、生物信息学、 生物统计学和临床研究设计；(2)在临床研究中扩展知识的正式教学论 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)前列腺癌的专业发展 过渡到独立，以及(5)R01应用程序的数据收集。一种导师关系和 多学科科学委员会已经成立，以促进提案的目标和 走向独立的进程。该计划将在加州大学旧金山分校实施 旧金山，提供卓越的研究环境、最先进的设施和支持性的 科学界将是促进职业发展和项目的理想环境 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.