Identifying Cooperating Mutations Contributing to Disease Progression in Mutant p53-Driven Breast Cancer

识别导致突变 p53 驱动的乳腺癌疾病进展的协同突变

• 批准号: 10212279
• 负责人: Rhiannon Morrissey
• 金额: $ 3.35万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212279
• 关键词: Adenoviruses; Advisory Committees; Arginine; Biological Models; Breast; Breast Cancer Model; Breast Carcinogenesis; Breast Carcinoma; Breast Epithelial Cells; Carcinoma; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Core Facility; DNA Binding Domain; Data; Development; Disease; Disease Progression; Duct (organ) structure; ERBB2 gene; Engineering; Enterobacteria phage P1 Cre recombinase; Environment; Epigenetic Process; Excision; Genes; Genetic; Genetic Models; Genomics; Goals; Hot Spot; Human; Human Genetics; Immune system; In Situ; In Situ Lesion; In Vitro; Inbred BALB C Mice; Incidence; Individual; Injections; Inter-tumoral heterogeneity; International; Invasive Lesion; Laboratories; Lead; Learning; Lesion; Malignant Neoplasms; Mammary Gland Parenchyma; Missense Mutation; Modeling; Mus; Mutate; Mutation; Noninfiltrating Intraductal Carcinoma; Operative Surgical Procedures; Pathologic; Pathway interactions; Process; Publications; Publishing; Radiation therapy; Research; Role; Scientist; System; TP53 gene; Techniques; Technology; Time; TimeLine; Tissues; Training; Tryptophan; Woman; Work; Writing; base; breast cancer progression; breast tumorigenesis; cancer genetics; cancer invasiveness; carcinogenesis; cohort; exome sequencing; human data; in vitro Model; in vivo; infiltrating duct carcinoma; insight; malignant breast neoplasm; mammary; mouse model; mutant; programs; symposium; transcriptome sequencing; transcriptomics; triple-negative invasive breast carcinoma; tumor; tumor heterogeneity; tumorigenesis; tumorigenic

PROJECT SUMMARY ABSTRACT Breast cancer progression is not a linear process; an in situ tumor does not always progress into an invasive lesion. It is difficult to predict which tumors will remain localized, and which will likely spread to other tissues. This problem is exacerbated because multiple genetic drivers can induce breast cancer. One such gene is p53; about 30% of breast cancers involve a missense mutation in the p53 DNA binding domain. The most common hot spot mutation in human cancers is at residue R248, orthologous to the mouse R245 residue. This mutation, often R245W (substituting arginine for tryptophan), induces invasive ductal carcinoma. Our laboratory maintains a mouse cohort with an Adenovirus-packaged Cre recombinase-induced conditional p53R245W mutation, with a median latency period of about 18 months until invasive carcinoma (IC) development. Pathological analysis of mammary tissue identified IC along with ductal carcinoma in situ (DCIS), allowing us to characterize the full spectrum of mutant p53-driven breast cancer progression. This project aims to define how mutant p53 drives DCIS development and progression into IC. Human sequencing data shows that breast cancer displays robust intertumoral heterogeneity, thus we hypothesize that mutant p53 drives initial tumorigenesis, and cooperates with additional mutations to drive the development from DCIS to IC. In Aim 1, we will characterize mutant p53-dependent DCIS progression in vivo. We will define a timeline of DCIS development and progression to IC, as well as exome sequencing and RNA sequencing DCIS and IC lesions to identify mutations and genes/pathways necessary for invasion. In Aim 2, we will investigate the mechanisms contributing to breast carcinoma disease progression, and functionally characterize cooperating lesions identified in Aim 1. This project will elucidate how an initial p53 mutation can induce DCIS development and progression to IC. Cooperating mutations will be characterized to distinguish those associated with a DCIS lesion that will remain localized from a DCIS lesion that is likely to progress to invasion. We aim to identify mutations cooperating with mutant p53 to drive invasion, to potentially elucidate strategies to stratify treatment for DCIS lesions, based on their genetic alterations. The Lozano laboratory at MD Anderson is the perfect environment for me to complete my project and learn mouse modeling and cancer genetics. During my graduate training, I will meet with my advisory committee as a group biannually, and individually as needed. I will write a review and 2 first-author publications, present my work regularly, and attend one national/international conference annually. I will have the opportunity to interact with world-class scientists at MD Anderson (including my Sponsor), and have access to state-of-the-art technology and core facilities. I will also participate in Genetics Department seminars, including weekly Research Exchange and Blaffer Seminars, to interact with scientists from around the nation. Through my graduate program, I'll receive extensive training in the fundamental concepts and applications of genetic and epigenetic principles.

项目概要摘要 乳腺癌的进展不是一个线性过程；原位肿瘤并不总是进展为侵袭性肿瘤 病变。很难预测哪些肿瘤将保持局部，哪些可能会扩散到其他组织。 由于多种基因驱动因素可以诱发乳腺癌，这个问题变得更加严重。 p53 就是这样的一个基因； 大约 30% 的乳腺癌涉及 p53 DNA 结合域的错义突变。最常见的 人类癌症的热点突变位于残基 R248，与小鼠 R245 残基直系同源。这种突变， 通常，R245W（用精氨酸代替色氨酸）会诱发浸润性导管癌。我们的实验室维护 具有腺病毒包装的 Cre 重组酶诱导的条件性 p53R245W 突变的小鼠群体，具有 发展为浸润性癌 (IC) 的中位潜伏期约为 18 个月。病理分析 乳腺组织鉴定出 IC 和导管原位癌 (DCIS)，使我们能够全面表征 突变 p53 驱动的乳腺癌进展谱。该项目旨在定义突变 p53 如何驱动 DCIS 的发展和进展为 IC。人类测序数据显示乳腺癌表现出强大的 肿瘤间异质性，因此我们假设突变型 p53 驱动初始肿瘤发生，并且 与其他突变合作，推动从 DCIS 到 IC 的发展。在目标 1 中，我们将 表征突变型 p53 依赖性 DCIS 体内进展。我们将确定 DCIS 开发的时间表 和进展至 IC，以及外显子组测序和 RNA 测序 DCIS 和 IC 病变，以识别 入侵所需的突变和基因/途径。在目标 2 中，我们将研究贡献的机制 乳腺癌疾病进展，并在功能上表征目标 1 中确定的协同病变。 该项目将阐明初始 p53 突变如何诱导 DCIS 发展和进展为 IC。 协同突变将被表征，以区分那些与 DCIS 病变相关的突变，这些病变将继续存在 源自导管原位癌 (DCIS) 病变，可能会进展为侵袭性。我们的目标是识别与合作的突变 突变 p53 驱动侵袭，有可能阐明 DCIS 病变分层治疗的策略，基于 他们的基因改变。 MD 安德森的 Lozano 实验室是我完成任务的完美环境 我的项目并学习小鼠建模和癌症遗传学。在我的研究生培训期间，我会遇到我的 咨询委员会作为一个小组，每两年举行一次，并根据需要单独举行一次。我会写一篇评论和2位第一作者 出版物，定期展示我的作品，并每年参加一次国内/国际会议。我会有 有机会与 MD 安德森的世界级科学家（包括我的赞助商）互动，并获得 拥有最先进的技术和核心设施。我还将参加遗传学系的研讨会，包括 每周的研究交流和布拉弗研讨会，与来自全国各地的科学家互动。通过我的 研究生课程中，我将接受有关遗传和遗传的基本概念和应用的广泛培训 表观遗传原理。