Core A: Molecular Pathology Core

项目摘要/摘要： 分子病理学核心的目标是：(I)为计划项目调查人员提供 获得高质量的、有临床注释的人类膀胱肿瘤，这些肿瘤代表了疾病的全部谱系， (Ii)协助调查人员获取人体膀胱癌以作分子研究和有机化合物研究 和(Iii)帮助研究膀胱的形态、组织病理学和基因组特征 肿瘤，包括那些出现在转基因小鼠模型(GEMM)中的肿瘤。核心A将扮演一个核心角色 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 通过对小鼠和人类肿瘤和有机物的组织学、分子和基因组分析，以及与 来自人类尿路上皮癌模型系统的分子研究结果的验证。特定的科学关注点 核心A将与项目调查人员合作，对时间序列进行分析，其中 人类膀胱癌中会出现基因组变化。核心的目标是：目标1：获取和维护 尿路上皮肿瘤的生物信息库，反映了疾病从早期的非 侵袭性肿瘤，到肌肉侵袭性原发肿瘤，再到转移性病变，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，以 确定膀胱癌突变事件的时间序列，重点关注 表观遗传调节基因，如KDM6A和ARID1A，以及与DNA修复和化疗相关的基因 响应，如ERCC2。Core还将从膀胱样本中构建组织微阵列，特别是 那些已经被表征为基因组改变的基因，以便于验证来自 人膀胱癌的GEMM和人体器官模型的研究。目标2：提供专家 患者和小鼠膀胱肿瘤的组织病理学评价和分子特征。 核心A将通过选择在小鼠和人类尿路上皮肿瘤的分子特征中发挥关键作用 要分析的最具代表性的肿瘤区域，并根据需要进行宏观或微观解剖 以丰富肿瘤内容，或将非侵袭性区域与侵袭性区域或形态截然不同的区域分开。核心A 还将协助项目调查人员对肿瘤进行基因组测序分析，以及 进行和解释H&E、免疫组织化学和原位杂交分析。 整合：每个项目都需要分子病理学核心的贡献才能实现他们提出的 研究目的。项目负责人将与Core合作，以获得和处理成对的非侵入性/有创性和 原发/转移样本和在患者病程的不同时间收集的样本以确定 膀胱癌发病过程中基因组改变发生的时间。该核心还将协助 GEMMS类有机物模型的组织病理学、形态和分子特征。

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.