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

项目总结摘要 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的。 损伤。很难预测哪些肿瘤将保持局部性，哪些可能会扩散到其他组织。 这一问题之所以恶化，是因为多种基因驱动因素都可能诱发乳腺癌。其中一个这样的基因是p53； 大约30%的乳腺癌涉及P53 DNA结合域的错义突变。最常见的 人类癌症中的热点突变位于残基R248，与老鼠的R245残基同源。这种突变， 通常，R245W(用精氨酸代替色氨酸)会导致浸润性导管癌。我们的实验室坚持认为 携带重组腺病毒包装的Cre重组酶诱导的条件突变p53R245W的小鼠队列，具有 浸润性癌(IC)发生前的中位潜伏期约为18个月。骨肉瘤的病理分析 乳腺组织发现IC和导管原位癌(DCIS)，使我们能够表征完整的 突变型P53驱动乳腺癌进展的谱系。该项目旨在定义突变型p53是如何驱动 DCIS的发展和向IC的进展。人类测序数据显示乳腺癌表现出强大的生命力 肿瘤间的异质性，因此我们假设突变型p53驱动最初的肿瘤形成，并且 与其他突变协同作用，推动DCIS向IC的发展。在目标1中，我们将 研究突变型p53依赖的DCIS在体内的进展。我们将确定DCIS开发的时间表 并进展为IC，以及外显子组测序和RNA测序以识别DCIS和IC病变 突变和入侵所必需的基因/途径。在目标2中，我们将调查导致 乳腺癌疾病进展，以及目标1中确定的协作性病变的功能特征。 这个项目将阐明最初的P53突变如何诱导DCIS的发展和进展为IC。 合作突变的特征将与那些与DCIS病变相关的突变区分开来 局限于可能进展为侵袭性的DCIS病变。我们的目标是识别与之合作的突变 突变型p53驱动侵袭，潜在阐明对DCIS病变进行分层治疗的策略，基于 他们的基因改变。MD Anderson的Lozano实验室是我完成任务的完美环境 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，每两年一次，并根据需要单独进行。我会写一篇评论和两篇第一作者 出版，定期介绍我的工作，每年参加一次国家/国际会议。我要一杯 有机会与MD Anderson(包括我的赞助商)的世界级科学家互动，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。通过我的 研究生计划，我将接受广泛的培训，在遗传和应用的基本概念和应用 表观遗传原理。

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.