Genetic Signatures of Preinvasive Breast Disease

浸润前乳腺疾病的遗传特征

基本信息

批准号：
7213718
负责人：
CAROL L ROSENBERG
金额：
$ 19.32万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-12 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7213718
关键词：
Address Antibodies Bayesian Analysis Bayesian Method Bioinformatics Breast Breast Cancer Genetics Breast Diseases Cancer Detection Cancer Etiology Carcinoma in Situ Cells Characteristics Chemopreventive Agent Critical Pathways Data Diagnosis Disease Epithelial Epithelium Evaluation Fibroblasts Fresh Tissue Genes Genetic Genetic Transcription Goals Histologic Human Hybridization Array Hyperplasia In Situ Lesion Intraductal Hyperplasia Invasive Knowledge Label Lesion Malignant Neoplasms Mammary Gland Parenchyma Methods Microarray Analysis Microdissection Molecular Molecular Abnormality Molecular Profiling Non-Invasive Lesion Noninfiltrating Intraductal Carcinoma Not Defined Oligonucleotide Microarrays Pathway interactions Play Population Premalignant Preventive Research Resources Role Seminal Series Staging Standards of Weights and Measures Stromal Cells Time Tissue-Specific Gene Expression Tissues Woman base breast cancer diagnosis breast lesion cancer cell cancer risk carcinogenesis in vivo insight malignant breast neoplasm novel outcome forecast prognostic repository tumor progression

项目摘要

DESCRIPTION (provided by applicant): With over 200,000 new cases diagnosed yearly, it is imperative to understand breast cancers' genetic causes and characteristics. Current understanding of non-invasive breast cancer is limited, and knowledge of premalignant disease is rudimentary. Yet knowledge of genetic abnormalities seminal to early stages of carcinogenesis is critical for estimating cancer risk, diagnosing premalignant lesions destined to progress, selecting potential targets for new preventive agents, and generating a comprehensive understanding of cancer etiology. To address this critical gap in knowledge of breast carcinogenesis, this application's objective is to evaluate RNA expression in early lesions from breast cancer-containing tissues. We will use microdissection and oligonucleotide microarrays to examine RNA expression in co-existing epithelium (normal, atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS)), and in stroma (fibroblasts and myoepithelium) surrounding each lesion. This project's rationale is the epidemiologic, histologic and genetic evidence that hyperplastic lesions may be non-obligate breast cancer precursors, and the growing data that the microenvironment plays a crucial role in tumor progression. However, the precise relationship between hyperplasias and cancers is not defined, and the role of the microenvironment in preinvasive disease is unexamined. Based on the existing evidence and our preliminary data, we speculate that distinct changes occur in the epithelium of these early lesions, and that the stroma surrounding normal and/or ADH lesions may also influence these lesions' progression. To accomplish our objective, we plan: Aim 1: Define RNA expression in preinvasive breast epithelium, a) obtain fresh tissue from 20 sporadic cancer cases, b) microdissect co-existing normal, ADH and DCIS lesions, extract and amplify RNA, perform array hybridizations, c) identify genes and pathways activated during progression using a novel bioinformatics method Bayesian Analysis of Differential Gene Expression (BADGE) and a traditional approach Significance Analysis of Microarrays (SAM) plus existing annotation resources. Aim 2: Define RNA expression in the stroma surrounding each epithelial lesion, a) from the same cases, isolate homogeneous cell populations in the surrounding stroma, b) extract and amplify RNA, perform array hybridizations, c) use BADGE, SAM and annotation resources to identify genes and pathways critical to the early stages of breast carcinogenesis.

描述（由申请人提供）：每年被诊断出200,000多个新病例，必须了解乳腺癌的遗传原因和特征。当前对非侵入性乳腺癌的理解是有限的，对疾病的知识是基本的。然而，对癌变的遗传异常到癌变的早期阶段的了解对于估计癌症风险，诊断原定为进步的病变，为新的预防剂选择潜在的靶标以及对癌症病因的全面了解至关重要。为了解决有关乳腺癌发生知识的这一关键差距，该应用的目标是评估含乳腺癌组织的早期病变中的RNA表达。我们将使用显微解剖和寡核苷酸微阵列来检查共存在的上皮（正常，非典型导管增生（ADH）和导管癌（DCIS）（DCIS）），以及周围每个Lesion的基质（成纤维细胞和肌上皮）。该项目的基本原理是增生性病变可能是非统治乳腺癌前体的流行病学，组织学和遗传学证据，而微环境在肿瘤进展中起着至关重要的作用，而增长的数据越来越不断增加。但是，增生和癌症之间的精确关系尚未定义，并且微环境在侵染前疾病中的作用尚未审查。根据现有的证据和我们的初步数据，我们推测这些早期病变的上皮发生了明显的变化，并且围绕正常和/或ADH病变的基质也可能影响这些病变的进展。 To accomplish our objective, we plan: Aim 1: Define RNA expression in preinvasive breast epithelium, a) obtain fresh tissue from 20 sporadic cancer cases, b) microdissect co-existing normal, ADH and DCIS lesions, extract and amplify RNA, perform array hybridizations, c) identify genes and pathways activated during progression using a novel bioinformatics method Bayesian Analysis of Differential Gene Expression （徽章）以及微阵列（SAM）以及现有注释资源的传统方法显着分析。 AIM 2：在每个上皮病变周围的基质中定义RNA表达，a）从同一情况下，分离出周围基质中的均匀细胞群，b）提取和放大RNA，进行阵列杂交，c）使用徽章，SAM，SAM，SAM和注释资源，以识别对早期乳腺癌的早期基因和途径。