Genetic Predictors of Progression of Premalignant Breast Disease

正常乳腺上皮的生长和分化受两条研究较多的分子信号通路的控制，这两条信号通路是由上皮生长因子(ERBB)和转化生长因子(TGF-B)介导的。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中也紧密交织在一起。这项研究的总体目标是通过研究明确定义的相互作用的ERBB和转化生长因子-B信号通路中的遗传变异如何与组织学定义的乳腺病变相互作用来影响乳腺癌风险，从而确定乳腺癌的预测因素。为了达到这一目标，我们对7923名因良性乳腺疾病接受活检的女性进行了全面的研究，其中529人患上了侵袭性乳腺疾病 随访期为癌或导管原位癌。该队列伴随着已确定的乳腺癌危险因素的流行病学数据、最初良性乳腺疾病活检的石蜡包埋组织块，以及首次活检和后续肿瘤的严格病理细节。 我们将对这些患者进行嵌套病例对照研究。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特征之间的相互作用提供取之不尽的资源。这一群体正在通过一项单独的R01赠款进行扩大。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个病例和1780个对照。我们的具体目标如下： 1.确定控制ERBB信号的基因如何相互作用以及与良性乳腺疾病如何影响乳腺癌风险。这一目标将集中在ERBB信号通路的核心基因上。我们将在600例患者和1200名对照中研究这一途径。我们将使用高效的标记SNPs来应用LD作图来捕捉每个座位的遗传多样性。 2.确定转化生长因子-β信号通路核心基因的多态如何相互作用，以及与良性乳腺疾病如何影响乳腺癌风险。这种做法将遵循目标1的做法。 3.定义所有完全连锁不平衡的变异，并直接标记每个单倍型 与乳腺癌的进展密切相关。在基因的所有其他变异中，这些基因变异的狭小子集是一组可能与乳腺癌病因学相关的候选基因。

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.