Genetic Predictors of Progression of Premalignant Breast Disease

正常乳腺上皮细胞的生长和分化受上皮细胞生长因子（ERBB）和转化生长因子（TGF-β）介导的两种分子信号通路的控制。受体家族这些途径在良性增生性乳腺疾病和乳腺癌的病因学中也紧密交织在一起。本研究的总体目标是通过研究明确的相互作用ERBB和TGF-β信号通路内的遗传变异如何与组织学定义的乳腺病变相互作用以影响乳腺癌风险来确定乳腺癌的预测因子。我们通过全面研究7,923名接受良性乳腺疾病活检的女性来实现这一目标，其中529名患有浸润性乳腺癌。 癌症或导管原位癌。该队列伴随着已建立的乳腺癌危险因素的流行病学数据，初始良性乳腺疾病活检的石蜡包埋组织块，以及初始活检和随后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。我们还寻求进行准确的全基因组扩增，这将为研究良性组织学和其他遗传性状之间的相互作用提供取之不尽的资源。这一群体正在通过单独的R 01赠款扩大。我们预计在未来五年内，我们的巢式病例对照研究将扩大到890例病例和1780例对照。我们的具体目标如下： 1.确定控制ERBB信号传导的基因如何相互作用以及与良性乳腺疾病相互作用以影响乳腺癌风险。本目标将集中在ERBB信号通路的核心基因。我们将在600例病例和1200例对照中研究该途径。我们将应用LD作图，使用有效的标签SNP来捕获每个位点的遗传多样性。 2.确定TGF-B信号通路中心基因的多态性如何相互作用以及与良性乳腺疾病相互作用以影响乳腺癌风险。该方法将遵循目标1的方法。 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。这些遗传变异的狭窄子集，以及基因上的所有其他变异，是一组可能与乳腺癌病因相关的候选者。

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-B.) 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-B 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-B 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.