Variation in Receptor Tyrosine Kinases and Breast Cancer Risk

酪氨酸激酶基因变异与乳腺癌风险 很明显，患乳腺癌的风险部分是由基因决定的。基因方面的贡献 乳腺癌的风险可能来自人群中常见或罕见的变异(或两者兼而有之)。为了 系统地评估常见和罕见的多态，我们建议应用结构化的和高度的 多学科双管齐下的方法，旨在最初最大限度地检测每个因素的影响 关于乳腺癌风险的变异类别。对于常见的变异，我们将重点放在癌症相关性的研究上 在护士健康研究中使用乳腺癌病例和对照的DNA，以及从 孢子的高危人群。更罕见的错义变体将受到功能性细胞和 分子分析，结合对家族性乳腺癌病例中变异的跟踪。任何变种， 积极的分数(对于功能或联想)将通过互补性方法来追求。在上一次 孢子周期，我们使用了乳腺腺泡的三维(3D)培养模型来鉴定来自 诱导与乳腺相关事件类似的表型变化的‘乳腺癌1000’cDNA文库 肿瘤的发生和发展。在这些结果的基础上，我们将首先关注四个候选受体 酪氨酸激酶，表现出最显著的表型效应：EGF-R，CSF-1R，ERBB2，ANC IGF-1。 1R。这种研究方法将在未来几年扩展到其他基因。在这项提案中，我们将 具体地说：1)测试常见的变异与乳腺癌之间的关联，跨越一系列风险类别，2) 测试罕见变异以区分功能活动及其与家族性和早发性乳房的相关性 癌症，3)检测基因变异与乳腺癌受体表达状态的关系。 散发性乳腺癌和4)在可能的情况下评估循环配体与这些疾病的相关性 受体和随后的乳腺癌风险。利用这一范式研究遗传变异的作用 对于乳腺癌，我们希望找出与乳腺癌风险相关的中等渗透性等位基因。

VARIATION IN RECPTOR TYROSINE KINASES AND BREAST CANCER RISK It is clear that part of the risk of developing breast cancer is genetically determined. The genetic contribution to breast cancer risk may arise from either common or rare variants (or both) in the population. In order to systematically assess both common and rare polymorphisms, we propose to apply a structured and highly multidisciplinary two pronged approach designed to initially maximize the power to detect the effect of each class of variants on breast cancer risk. For the common variants, we will focus on cancer association studies using DNA from breast cancer cases and controls in the Nurses' Health Study and breast cancer cases from the SPORE's High Risk Cohort. The rarer missense variants will be subjected to functional cellular and molecular assays, combined with tracking of the variants in cases of familial breast cancer. Any variant that scores positive (for function or association) will be pursued by the complementary approach. In the previous SPORE cycle, we employed a 3-dimensional (3D) culture model of breast acini to identify genes from the 'Breast Cancer 1000' cDNA library that induce phenotypic changes resembling events associated with breast tumor initiation and progression. Building on these results, we will initially focus on four candidate receptor tyrosine kinases, which showed the most dramatic phenotypic effects: EGF-R, CSF-1R, ERBB2, anc IGF- 1R. This research approach will be extended to other genes in future years. In this proposal, we wilt specifically: 1) test common variants for association with breast cancer across a spectrum of risk classes, 2) test rare variants for distinguishable functional activity and association with familial and early-onset breast cancer, 3) examine the relationship between genetic variation and breast tumor receptor expression status in sporadic breast cancer and 4) when possible evaluate the association of circulating ligands for these receptors and subsequent breast cancer risk. Using this paradigm to investigate the role of genetic variation and breast cancer, we hope to identify modestly penetrant alleles conferring breast cancer risk.