Genomics Core

基因组学核心

• 批准号: 10003309
• 负责人: David B Solit
• 金额: $ 52.11万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10003309
• 关键词: Aftercare; Alleles; Area Analyses; BRCA2 gene; Bioinformatics; Biological; Biological Assay; Biological Markers; Biometry; Biopsy; CDH1 gene; Cancer Patient; Clinical; Clinical Trials; Cohort Analysis; Collaborations; Communities; Consent; DNA; DNA Repair; DNA Sequence Alteration; DNA sequencing; Dana-Farber Cancer Institute; Data; Data Analyses; Data Set; Decision Making; Deposition; Diagnosis; Disease; Doctor of Philosophy; Drug resistance; Engineering; Enrollment; Ensure; Ethnic group; Formalin; Gene Mutation; Genes; Genomic Data Commons; Genomics; Germ-Line Mutation; Goals; Heritability; Human Resources; Individual; Inherited; Institutional Review Boards; Link; Malignant neoplasm of prostate; Mediating; Memorial Sloan-Kettering Cancer Center; Mission; Molecular; Molecular Analysis; Molecular Profiling; Monitor; Mutation; Normal tissue morphology; Outcome; PARP inhibition; Paraffin Embedding; Pathogenicity; Pathologist; Pathology; Pathway interactions; Patient Monitoring; Patients; Plasma; Prostatic Neoplasms; Protocols documentation; Publishing; Research; Research Personnel; Research Project Grants; Residual Neoplasm; Resistance; Risk; Running; Sampling; Somatic Mutation; Surgical Pathology; Testing; Time; Tissue Embedding; Training; Tumor Tissue; Validation; Variant; Work; authority; cBioPortal; cancer genetics; cancer genomics; cancer risk; castration resistant prostate cancer; cell free DNA; cellular engineering; clinically relevant; clinically significant; cohort; data resource; data sharing; data visualization; database of Genotypes and Phenotypes; exome; exome sequencing; experience; gene repair; genome sequencing; genomic data; high risk; hormone therapy; improved; inhibitor/antagonist; men; molecular oncology; mutant; neoplastic cell; next generation sequencing; novel; patient screening; programs; prospective; prostate cancer cell; prostate cancer model; prostate cancer risk; public repository; response; standard of care; success; targeted sequencing; therapy resistant; transcriptome sequencing; treatment response; treatment strategy; tumor; tumor DNA; whole genome

ABSTRACT The objectives of the Genomics Core are 1) to perform prospective and retrospective molecular analysis of prostate tumors, cell-free DNA (cfDNA) and germline DNA to facilitate the aims of the P01 and 2) to facilitate sharing of genomic data and linked clinical annotation among the P01 investigators and with the broader scientific community. To achieve these objectives, the Genomics Core includes personnel trained in cancer genetics, surgical pathology, biostatistics, bioinformatics, and genomic data sharing. The Genomics Core has three aims. First, to aid in the identification of germline mutations associated with increased heritable risk or poor long-term clinical outcomes, the Genomics Core will conduct targeted sequencing of 250 DNA damage repair (DDR) pathway genes or WES of prostate cancer tumors and matched germline DNA (Project 1) from men with prostate cancer for whom we have long-term clinical outcomes data. To further facilitate the identification of novel germline mutations that associate with increased heritable risk or poor clinical outcomes, all sequencing data generated as part of this P01 will be integrated in real-time with published datasets and unpublished genomic data from ongoing profiling initiatives at Memorial Sloan Kettering Cancer Center (MSK- IMPACT) and Dana-Farber Cancer Institute (DFCI-Profile). Second, the core will explore mechanisms of treatment resistance by analyzing tumors and cfDNA collected before and after PARP inhibitor treatment from patients enrolled on the MetaCURE clinical trial platform (Project 2). This latter aim required the Genomics Core to develop a cfDNA assay (MSK-ACCESS) that could be used to monitor patients for minimal residual disease and could also identify mutations that mediate response and resistance to PARP inhibition. Third, the core will facilitate data sharing both within the P01 and with the broader research community, including the NCI. All three research projects are highly integrated with and rely extensively on the Genomics Core to achieve their proposed aims. More specifically, the core will assist Project 1 by sequencing (targeted and whole exome) germline and, in some cases, matched tumor DNA from several large cohorts of annotated patient samples to identify alterations in DDR pathway genes. The core will also provide real-time access to the germline data generated by MSK-IMPACT and DFCI-Profile. The core will assist Project 2 by screening patients for DDR aberrations and with the analysis of tumor samples and cfDNA collected before and after PARP inhibitor treatment to monitor treatment response and to explore mechanisms of drug resistance. The core will work with Project 3 to perform molecular analyses of cells engineered to harbor deleterious BRCA2 or ATM alleles or in which ATM or CDH1 have been deleted. Finally, the Genomics Core will help all three projects make predictions about the pathogenicity of individual mutations to facilitate data interpretation, study enrollment, and prioritization of mutants for functional characterization.

抽象的 基因组学核心的目标是 1) 进行前瞻性和回顾性分子分析 前列腺肿瘤、游离 DNA (cfDNA) 和种系 DNA，以促进 P01 和 2) 的目标 在 P01 研究人员之间以及更广泛的范围内共享基因组数据和相关临床注释 科学界。为了实现这些目标，基因组学核心包括接受过癌症培训的人员 遗传学、外科病理学、生物统计学、生物信息学和基因组数据共享。基因组学核心有 三个目标。首先，帮助识别与遗传风险增加相关的种系突变或 长期临床结果不佳，Genomics Core 将对 250 个 DNA 损伤进行靶向测序 前列腺癌肿瘤的修复 (DDR) 途径基因或 WES 以及匹配的种系 DNA（项目 1） 我们拥有长期临床结果数据的前列腺癌男性。为进一步便利 识别与遗传风险增加或临床结果不良相关的新种系突变， 作为 P01 一部分生成的所有测序数据将与已发布的数据集实时集成， 纪念斯隆凯特琳癌症中心 (MSK- IMPACT）和达纳法伯癌症研究所（DFCI-Profile）。二是核心将探索机制 通过分析 PARP 抑制剂治疗前后收集的肿瘤和 cfDNA 来确定治疗耐药性 患者参加了 MetaCURE 临床试验平台（项目 2）。后一个目标需要基因组学 开发可用于监测患者微量残留的 cfDNA 检测 (MSK-ACCESS) 的核心 疾病，还可以识别介导对 PARP 抑制的反应和抵抗的突变。第三， 核心将促进 P01 内部以及与更广泛的研究界（包括 国家癌症研究所。所有三个研究项目都与基因组学核心高度集成并广泛依赖 实现他们提出的目标。更具体地说，核心将通过排序（有针对性的和 全外显子组）种系，在某些情况下，与来自几个大组注释的肿瘤DNA相匹配 患者样本以确定 DDR 通路基因的改变。该核心还将提供对 由 MSK-IMPACT 和 DFCI-Profile 生成的种系数据。核心将通过筛选协助项目2 患者的 DDR 畸变以及前后收集的肿瘤样本和 cfDNA 分析 PARP 抑制剂治疗可监测治疗反应并探索耐药机制。这 core 将与 Project 3 合作，对含有有害 BRCA2 的细胞进行分子分析 或 ATM 等位基因，或其中 ATM 或 CDH1 已被删除。最后，基因组学核心将帮助这三个方面 项目对个体突变的致病性进行预测，以促进数据解释和研究 突变体的登记和优先排序以进行功能表征。