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: 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
• 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

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 乳腺癌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。 损伤。很难预测哪些肿瘤将保持局部化，哪些可能会扩散到其他组织。 这个问题加剧了，因为多种遗传驱动因素可以诱发乳腺癌。一个这样的基因是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在残基R248处，与小鼠R245残基相邻。这种突变 通常为R245 W（精氨酸取代色氨酸），诱导浸润性导管癌。我们的实验室 具有腺病毒包装的Cre重组酶诱导的条件性p53 R245 W突变的小鼠队列， 中位潜伏期约为18个月，直至发生浸润性癌（IC）。病理分析 乳腺组织沿着导管内原位癌（DCIS），使我们能够描述完整的 突变型p53驱动的乳腺癌进展谱。该项目旨在确定突变的p53如何驱动 DCIS的发展和IC的进展。人类测序数据显示，乳腺癌显示出强大的 肿瘤间异质性，因此我们假设突变型p53驱动初始肿瘤发生， 与其他突变合作，推动从DCIS到IC的发展。在目标1中，我们 在体内表征突变型p53依赖性DCIS进展。我们将确定DCIS开发的时间轴 以及外显子组测序和RNA测序DCIS和IC病变， 入侵所必需的突变和基因/途径。在目标2中，我们将研究影响的机制 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。 本项目将阐明初始p53突变如何诱导DCIS发展和进展为IC。 将对协同突变进行表征，以区分与DCIS病变相关的突变， 可能进展为浸润的DCIS病变。我们的目标是找出突变合作， 突变p53驱动侵袭，潜在阐明DCIS病变分层治疗策略，基于 他们的基因改变MD安德森的洛萨诺实验室对我来说是完成 我的项目，学习老鼠建模和癌症遗传学。在我的研究生培训期间，我将与我的 咨询委员会作为一个小组每两年举行一次，并根据需要单独举行。我会写一篇评论和2个第一作者 出版物，定期介绍我的工作，每年参加一次国家/国际会议。我将不得不 有机会与MD安德森的世界级科学家（包括我的赞助商）互动，并有机会访问 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Blaffer研讨会，与来自全国各地的科学家互动。通过我 在研究生课程中，我将接受遗传学的基本概念和应用方面的广泛培训， 表观遗传学原理