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

基本信息

批准号：
10413028
负责人：
Rhiannon Morrissey
金额：
$ 2.99万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
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/10413028
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

项目摘要

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.

项目摘要摘要乳腺癌进展不是线性过程。原位肿瘤并不总是发展为侵入性病变。很难预测哪些肿瘤将保持定位，哪些肿瘤可能会扩散到其他组织。这个问题加剧了，因为多个遗传驱动因素可以诱导乳腺癌。这样的基因是p53；约30％的乳腺癌涉及p53 DNA结合结构域中的错义突变。最常见的人类癌症中的热点突变处于残基R248，与小鼠R245残基的直源。这个突变，通常R245W（将精氨酸取代色氨酸）诱导浸润性导管癌。我们的实验室坚持认为带有腺病毒包装的CRE重组酶诱导的条件p53R245W突变的小鼠队列，带有A 中位潜伏期约18个月，直到浸润性癌（IC）发育。病理分析乳腺组织与原位导管癌一起鉴定出IC，使我们能够表征完整突变体p53驱动的乳腺癌进展的频谱。该项目旨在定义突变体p53如何驱动 DCIS的发展和发展为IC。人类测序数据表明，乳腺癌显示出强大的肿瘤间异质性，因此我们假设突变体p53驱动初始肿瘤发生，并且与其他突变合作，以推动从DCI到IC的发展。在AIM 1中，我们将表征了体内突变体p53依赖性DCIS的进展。我们将定义DCIS开发的时间表以及进展到IC，以及外显子组测序和RNA测序DCI和IC病变，以鉴定突变和侵袭所需的基因/途径。在AIM 2中，我们将研究促成的机制乳腺癌疾病进展，并在功能上表征AIM 1中确定的合作病变。该项目将阐明最初的p53突变如何诱导DCIS的发展和进展到IC。合作的突变将被特征为区分与DCIS病变相关的突变从DCIS病变中局部，可能会发展为入侵。我们旨在确定与合作的突变突变体p53以推动入侵，以根据基于他们的遗传改变。 MD Anderson的Lozano实验室是我完成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，我将与我的咨询委员会每两人小组，单独根据需要单独。我将写评论和2位第一职业者出版物，定期介绍我的作品，并每年参加一次国家/国际会议。我会的与MD Anderson（包括我的赞助商）的世界一流科学家互动的机会，并可以访问到最先进的技术和核心设施。我还将参加遗传学系研讨会，包括每周研究交流和布拉夫研讨会，与来自全国各地的科学家互动。通过我的研究生课程，我将获得有关遗传和应用的基本概念和应用的广泛培训表观遗传原则。