Genetic Predictors of Progression of Premalignant Breast Disease

癌前乳腺疾病进展的遗传预测因素

• 批准号: 7515264
• 负责人: Jeffrey R. Smith
• 金额: $ 23.39万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-11 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7515264
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Affect; Alleles; Benign; Biological Process; Biopsy; Breast; Breast Cancer Risk Factor; Breast Diseases; Complex; Data; Development; Differentiation and Growth; EGFR gene; Elevation; Epidermal Growth Factor; Epithelial; Etiology; Family; Funding; Future; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Grant; Growth Factor; Haplotypes; Histologic; Histology; Individual; International; Intervention; Invasive; Investigation; Linkage Disequilibrium; Linkage Disequilibrium Mapping; Mediating; Molecular; Nested Case-Control Study; Noninfiltrating Intraductal Carcinoma; Numbers; Other Genetics; Paraffin Embedding; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Premalignant; Process; Proliferative Type Breast Fibrocystic Change; Protein Kinase C; Recording of previous events; Resources; Risk; Role; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; System; Testing; Thinking; Tissues; Transforming Growth Factors; Variant; Woman; base; breast lesion; cancer risk; cohort; follow-up; genetic epidemiology; genetic variant; malignant breast neoplasm; multidisciplinary; novel therapeutics; receptor; therapeutic target; trait; tumor

Normal breast epithelial growth and differentiation is under the control of two well-studied molecular signaling pathways mediated by the epithelial growth factor (ERBB) and transforming growth factor (TGF-¿.) receptor families. These pathways are also closely intertwined in the etiology of benign proliferative breast disease and breast cancer. The overall objective of this study is to identify predictors of breast cancer by investigating how genetic variation within the well-defined interacting ERBB and TGF-¿ signaling pathways interact with histologically defined breast lesions to affect breast cancer risk. We approach this objective by comprehensively studying a unique cohort of 7,923 women who underwent biopsy for benign breast disease, 529 of whom have developed invasive breast cancer or ductal carcinoma in situ during follow-up. The cohort is accompanied by epidemiological data of established breast cancer risk factors, paraffin-embedded tissue blocks of the initial benign breast disease biopsy, and rigorous pathologic detail of both the initial biopsy and subsequent tumor. We will conduct nested case-control studies on these patients. We also seek to perform an accurate whole genome amplification, which will provide an inexhaustible resource for investigating interactions between benign histology and other genetic traits. This cohort is being expanded through a separate R01 grant. We expect that over the next five years our nested case control study will expand to 890 cases and 1780 controls. Our specific aims are as follows: 1. To determine how genes that control ERBB signaling interact with each other and with benign breast disease to affect breast cancer risk. This Aim will focus on genes central to the ERBB signaling pathway. We will investigate the pathway in 600 cases and 1200 controls. We will apply LD mapping using efficient tagging SNPs to capture genetic diversity of each locus. 2. To determine how polymorphisms in genes central to the TGF-¿ signaling pathways interact with each other and with benign breast disease to affect breast cancer risk. The approach will follow that of Aim 1. 3. To define all variants in full linkage disequilibrium and that directly mark each haplotype significantly associated with progression to breast cancer. The narrow subset of these genetic variants, among all others at the gene, is a set of candidates that may be etiologically associated with breast cancer.

正常乳腺上皮细胞的生长和分化是在两种研究充分的分子调控下进行的。 上皮生长因子（ERBB）和转化生长因子介导的信号通路 (TGF-¿.）受体家族这些途径在良性肿瘤的病因学中也密切相关。 增生性乳腺疾病和乳腺癌。本研究的总体目标是确定 乳腺癌的预测因素，通过研究基因变异如何在明确的相互作用， ERBB和TGF-β信号通路与组织学定义的乳腺病变相互作用，影响乳腺癌的发生。 癌症风险。我们通过全面研究一个独特的7923人的队列来实现这一目标 因良性乳腺疾病接受活检的女性，其中529例发生浸润性乳腺癌 癌症或导管原位癌。该队列伴随着流行病学 已确定的乳腺癌风险因素数据，初始良性肿瘤的石蜡包埋组织块， 乳腺疾病活检，以及初始活检和后续肿瘤的严格病理细节。 我们将对这些患者进行巢式病例对照研究。我们还寻求执行一个准确的 全基因组扩增，这将为研究相互作用提供取之不尽的资源 良性组织学和其他遗传特征之间的联系这一群体正在通过一个单独的 R 01格兰特。我们预计在未来五年内，我们的嵌套病例对照研究将扩大到890例 病例组和对照组1780例。我们的具体目标如下： 1.为了确定控制ERBB信号传导的基因如何相互作用以及与良性肿瘤的相互作用， 乳腺疾病影响乳腺癌风险。本目标将集中于ERBB的核心基因 信号通路我们将在600例病例和1200例对照中研究该途径。我们将应用 使用有效标记SNP的LD作图以捕获每个位点的遗传多样性。 2.确定TGF-²信号通路核心基因的多态性如何与 良性乳腺疾病相互影响乳腺癌的风险。该方法将遵循以下原则： 目标1。 3.确定完全连锁不平衡中的所有变异，并直接标记每个单倍型 与乳腺癌进展显著相关。这些基因的一小部分 在基因的所有其他变异中，变异是一组可能与病原学相关的候选者。 患有乳腺癌