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

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

项目成果

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Rhiannon Morrissey其他文献

Rhiannon Morrissey的其他文献

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{{ truncateString('Rhiannon Morrissey', 18)}}的其他基金

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
  • 财政年份:
    2020
  • 资助金额:
    $ 3.35万
  • 项目类别:
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:
    10062646
  • 财政年份:
    2020
  • 资助金额:
    $ 3.35万
  • 项目类别:

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