Genomics Core

基因组学核心

• 批准号: 10708058
• 负责人: David B Solit
• 金额: $ 51.43万
• 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/10708058
• 关键词: Aftercare; Alleles; Area Analyses; Authorization documentation; 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 Population; 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; Poly(ADP-ribose) Polymerase Inhibitor; 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; men; molecular oncology; mutant; next generation sequencing; novel; participant enrollment; patient screening; programs; prospective; 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.

摘要 基因组学核心的目标是1)进行前瞻性和回溯性的分子分析 前列腺癌、无细胞DNA(CfDNA)和生殖系DNA促进P01和2)的目的 在P01研究人员和更广泛的人之间共享基因组数据和相关的临床注释 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。基因组学核心已经 三个目标。首先，为了帮助识别与可遗传风险增加或 长期临床结果不佳，基因组学核心将对250个DNA损伤进行定向测序 前列腺癌肿瘤的修复(DDR)途径基因或WES与匹配的生殖系DNA(项目1)来自 我们有前列腺癌患者的长期临床结果数据。为进一步便利 识别与遗传风险增加或临床结果差相关的新的生殖系突变， 作为本P01的一部分生成的所有测序数据将与已发布的数据集和 来自纪念斯隆·凯特琳癌症中心(MSK-)正在进行的侧写倡议的未公布的基因组数据 Impact)和Dana-Farber癌症研究所(DFCI-Profile)。第二，核心将探索 用PARP抑制剂治疗前后收集的肿瘤和cfDNA分析耐药 参加MetaCURE临床试验平台的患者(项目2)。后一个目标需要基因组学 CORE开发一种cfDNA分析(MSK-ACCESS)，可用于监测患者的最小残留 还可以确定介导对PARP抑制的反应和抗性的突变。第三， CORE将促进P01内部以及与更广泛的研究社区的数据共享，包括 美国国家情报局。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于 实现他们提出的目标。更具体地说，核心将通过排序协助项目1(有针对性和 整个外显子组)胚系，在某些情况下，来自几个大的注释队列的肿瘤DNA 患者样本以确定DDR途径基因的变化。该核心还将提供实时访问 由MSK-IMPACT和DFCI-PROFILE生成的生殖系数据。核心将通过筛选来协助项目2 患者DDR异常及治疗前后肿瘤标本和cfDNA分析 PARP抑制剂治疗监测治疗反应，探讨耐药机制。这个 CORE将与Project 3合作，对携带有害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家公司 研究称，项目对个体突变的致病性进行预测以便于数据解释 登记，并确定突变体的优先顺序，以进行功能表征。