Core A: Molecular Pathology Core

核心 A：分子病理学核心

基本信息

批准号：
10218082
负责人：
Hikmat Al-Ahmadie
金额：
$ 24.94万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-11 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218082
关键词：
ARID1A gene Abate Academic Medical Centers Address Bioinformatics Biological Assay Biological Models Biometry Bladder Bladder Neoplasm Cancer Patient Clinical Clinical Research Collaborations DNA Repair DNA Sequence Alteration Disease Disease Progression ERCC2 gene Epigenetic Process Evaluation Event Evolution Generations Genetic Genetically Engineered Mouse Genitourinary system Genomics Goals Histologic Human Human Biology In Situ Hybridization Individual Laboratories Malignant Neoplasms Malignant neoplasm of prostate Malignant neoplasm of urinary bladder Memorial Sloan-Kettering Cancer Center Metastatic to Methods Microdissection Modeling Molecular Molecular Analysis Molecular Biology Morphology Mus Muscle Mutation Neoplasm Metastasis Organoids Pathogenesis Pathologist Pathology Patients Play Population Heterogeneity Primary Neoplasm Principal Investigator Process Prognostic Marker Regulator Genes Research Research Personnel Role Sampling Specimen Surgical Pathology The Cancer Genome Atlas Time Tissue Microarray Tissues Tumor Biology Tumor Tissue Urothelium Validation Work base biobank cancer subtypes chemotherapy clinical investigation ethnic diversity gender diversity human disease human model human tissue interest loss of function molecular pathology mouse model muscle invasive bladder cancer next generation sequencing novel therapeutic intervention patient population pre-clinical predictive marker programs response tumor

项目摘要

Project Summary/Abstract: The objectives of the Molecular Pathology Core are: (i) to provide Program Project investigators with access to high-quality, clinically-annotated human bladder tumors that represent the full spectrum of the disease, (ii) to assist investigators with acquisition of human bladder tumors for molecular studies and organoid generation, and (iii) to assist with the morphologic, histopathologic, and genomic characterization of bladder tumors, including those that arise in genetically-engineered mouse models (GEMMs). Core A will play a central role in collecting, annotating, storing, and distributing human tissues as required for each Project, and will assist with histologic, molecular, and genomic analyses of murine and human tumors and organoids, and with the validation of molecular findings from model systems to human urothelial cancer. The particular scientific focus of Core A will be to work with Program investigators to pursue analysis of the temporal sequence in which genomic alterations arise in human bladder cancer. The Aims of the Core are: Aim 1: To acquire and maintain a biorepository of urothelial tumors that reflects all states of disease progression from early non- invasive tumors, to muscle-invasive primary tumors to metastatic lesions, and that reflects the ethnic and gender diversity of patients with urothelial tumors. The Core will work with Program investigators to define the temporal sequence of mutational events in bladder cancer, with a focus on the timing of mutations in epigenetic regulators, such as KDM6A and ARID1A, and genes associated with DNA repair and chemotherapy response, such as ERCC2. The Core will also construct tissue microarrays from bladder specimens, particularly those that have been characterized for genomic alterations, to facilitate validation of key molecular findings from studies of GEMMs and human organoid models to human bladder cancer. Aim 2: To provide expert histopathologic evaluation and molecular characterization of bladder tumors from patients and mice. Core A will play a key role in the molecular characterization of mouse and human urothelial tumors by selecting the most representative tumor regions to be analyzed and by performing macro- or microdissection as needed to enrich for tumor content or to separate non-invasive from invasive or morphologically distinct regions. Core A will also assist the Program investigators with genomic sequencing analyses of tumors, as well as with performing and interpreting H&E, immunohistochemical, and in situ hybridization assays. Integration: Each Project will require contribution from the Molecular Pathology Core to achieve their proposed research aims. Project Leaders will work with the Core to obtain and process paired non-invasive/invasive and primary/metastatic samples and samples collected at distinct times in a patient's disease course to define the timing at which genomic alterations arise during bladder cancer pathogenesis. The Core will also assist in the histopathologic morphologic and molecular characterization of GEMMs organoid models.

项目摘要/摘要：分子病理学核心的目标是： (i) 为项目研究人员提供获得代表该疾病全谱的高质量、经过临床注释的人类膀胱肿瘤， (ii) 协助研究人员获取人类膀胱肿瘤用于分子研究和类器官 (iii) 协助膀胱的形态学、组织病理学和基因组表征肿瘤，包括基因工程小鼠模型（GEMM）中出现的肿瘤。核心A将扮演核心角色根据每个项目的需要，在收集、注释、存储和分发人体组织方面发挥作用，并将协助对鼠类和人类肿瘤及类器官进行组织学、分子和基因组分析，以及验证人类尿路上皮癌模型系统的分子发现。特定的科学焦点核心 A 的任务是与计划研究人员合作，对时间序列进行分析，其中人类膀胱癌中出现基因组改变。核心目标是：目标 1：获取和维护尿路上皮肿瘤的生物储存库，反映了从早期非进展到疾病进展的所有状态侵袭性肿瘤，肌肉侵袭性原发性肿瘤，转移性病变，这反映了种族尿路上皮肿瘤患者的性别多样性。核心将与计划调查人员合作定义膀胱癌突变事件的时间顺序，重点是突变的时间表观遗传调节因子，例如 KDM6A 和 ARID1A，以及与 DNA 修复和化疗相关的基因响应，例如 ERCC2。该核心还将利用膀胱标本构建组织微阵列，特别是那些已被表征为基因组改变的基因组，以促进关键分子发现的验证针对人类膀胱癌的 GEMM 和人类类器官模型的研究。目标2：提供专家患者和小鼠膀胱肿瘤的组织病理学评估和分子特征。 Core A 将通过选择在小鼠和人类尿路上皮肿瘤的分子表征中发挥关键作用要分析的最具代表性的肿瘤区域，并根据需要进行宏观或显微解剖丰富肿瘤内容或将非侵入性区域与侵入性或形态上不同的区域分开。核心A 还将协助该计划研究人员进行肿瘤基因组测序分析，以及执行和解释 H&E、免疫组织化学和原位杂交测定。整合：每个项目都需要分子病理学核心的贡献才能实现其提议的目标研究目的。项目负责人将与核心合作，获取并处理配对的非侵入性/侵入性和原发性/转移性样本以及在患者病程中不同时间收集的样本，以确定膀胱癌发病机制中基因组改变发生的时间。该核心还将协助 GEMM 类器官模型的组织病理学形态学和分子特征。