Establishing Genetic Drivers of Breast Cancer Metastases

建立乳腺癌转移的遗传驱动因素

基本信息

批准号：
8982375
负责人：
Marni B Siegel
金额：
$ 4.11万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8982375
关键词：
Address Automobile Driving Autopsy Biology Blood Circulation Brain Breast Cancer Cell Breast cancer metastasis Cancer Etiology Candidate Disease Gene Cell Line Cessation of life Clinical Collection DNA DNA copy number Data Data Set Development Disease Distant Environment Event Fellowship Foundations Funding Future Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Genomics Goals Growth Human Individual Injection of therapeutic agent Laboratories Literature MDA MB 231 Maps Mentors Metastatic breast cancer Metastatic malignant neoplasm to brain Modeling Molecular Mus Mutation Neoplasm Metastasis Non-Malignant Organ Outcome Pathway interactions Patients Pattern Physicians Point Mutation Population Primary Neoplasm Protocols documentation Publishing RB1 gene RNA Relative (related person)Risk Scientist Seeds Signal Transduction Site Somatic Mutation Systemic Therapy Testing The Cancer Genome Atlas Therapeutic Time Tissues Training Trees United States Variant Woman Work brain tissue career exome sequencing human tissue improved in vivo in vivo Model laser capture microdissection malignant breast neoplasm metastatic process mortality mouse model new therapeutic target outcome forecast prevent protein expression protein protein interaction public health relevance therapeutic development therapeutic target transcriptome sequencing tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Metastatic breast cancer is the leading cause of breast cancer-related deaths. Predictive signatures for poor prognosis breast cancer are available and routinely employed in the clinical setting; however, these signatures describe the risk of metastasis, not the underlying biologic drivers of metastasis. Moreover, accompanying therapeutic approaches to prevent metastasis are not provided by these established signatures. The underlying biology driving metastasis is largely unknown. Identifying genetic drivers of metastatic breast cancer and the timing during which these changes occur is critical to the development of effective therapeutics to prevent and treat metastases; such a study has yet to be performed in human tissues. We hypothesize that specific genetic and/or genomic factors are specifically enriched in breast cancer metastasis, and that some metastatic features are established within primary tumors. Utilizing a Rapid Autopsy Protocol established at UNC Chapel Hill, we have collected 169 metastatic breast cancer tissues from 34 individuals and performed RNA and DNA whole exome sequencing. Aim 1 will define those genetic features enriched in metastases through a statistical comparison of DNA copy number, point mutations, and RNA gene expression changes in metastatic breast cancer tissues as compared to 1000 primary breast cancers previously published through the Cancer Genome Atlas. Aim 1C will then compare DNA copy number alterations and point mutations for each individual patient's collection of metastases to establish a map of the acquisition of molecular changes across time. Patients with breast cancer brain metastases have extremely limited survival and no approved systemic therapies. Current literature from in vivo modeling suggests that significant changes to both breast cancer cells and the tumor microenvironment are critical for metastatic seeding and growth. Aim 2 will establish specific genetic features of breast cancer brain metastasis and the altered signaling in the supporting adjacent brain parenchyma. Comparing gene expression in adjacent non-malignant brain parenchyma to matched distant brain parenchyma both in human tissues and in two in vivo breast cancer brain metastasis models will identify supporting microenvironment signals unique to the adjacent brain parenchyma. Our goal is to identify genetic features enriched in breast cancer metastasis, ultimately to define future therapeutic targets and help decrease mortality from breast cancer. Along with the superb environment at UNC Chapel Hill, exceptional mentoring by Dr. Perou and Dr. Anders, and a comprehensive training plan, this fellowship will provide a critical foundation to build my future career as an independently funded physician-scientist in the field of cancer metastases.

描述（适用提供）：转移性乳腺癌是与乳腺癌相关死亡的主要原因。预后不良的乳腺癌的预测特征可在临床环境中使用并经常使用；但是，这些特征描述了转移的风险，而不是转移的基本生物驱动因素。此外，这些既定的签名没有提供参与预防转移的治疗方法。驱动转移的基本生物学基本上未知。鉴定转移性乳腺癌的遗传驱动因素以及这些变化发生的时间对于预防和治疗转移的有效疗法至关重要。这样的研究尚未在人体组织中进行。我们假设特定的遗传和/或基因组因子在乳腺癌转移中特异性富集，并且在原发性肿瘤中建立了一些转移性特征。利用在UNC Chapel山建立的快速尸检方案，我们从34个个体收集了169个转移性乳腺癌组织，并进行了RNA和DNA整个外显子组测序。 AIM 1将通过对转移性乳腺癌组织中的DNA拷贝数，点突变和RNA基因表达变化的统计比较来定义富含转移中的遗传特征，而先前通过癌症基因组图群发表的1000个原发性乳腺癌。然后，AIM 1C将比较每个患者收集转移酶的DNA拷贝数改变和点突变，以建立跨时间的分子变化的获取图。患有乳腺癌脑转移的患者的生存率极有限，没有批准的全身疗法。当前来自体内建模的文献表明，乳腺癌细胞和肿瘤微环境的显着变化对于转移性播种和生长至关重要。 AIM 2将建立乳腺癌脑转移的特定遗传特征，并在辅助相邻的脑实质中改变信号传导。在相邻的非恶性脑实质中的基因表达与人体组织中的不同脑实质和两个体内乳腺癌脑转移模型中的不同脑实质相匹配，将确定支持微环境信号，是相邻脑实质所特有的。我们的目标是确定富含乳腺癌转移的遗传特征，最终定义未来的治疗靶标，并有助于降低乳腺癌的死亡率。除了UNC Chapel Hill的精湛环境，Perou博士和Anders博士的出色心理以及全面的培训计划外，该奖学金将为建立我作为癌症转移领域独立资助的身体科学家的未来职业的关键基础。