The IGF Signaling Pathway and Breast Cancer Risk

描述(申请人提供)：乳腺癌是女性中最常见的癌症，发病率和死亡率都很高。我们假设参与胰岛素样生长因子(IGF)信号转导的基因变异在乳腺癌病因中起关键作用。IGF途径调节细胞生长，由于不受控制的细胞生长是癌症的标志，这一途径是一个关键组成部分。我们建议通过一种方法对参与IGF信号转导的基因进行全面的分析，该方法将多个变种结合到单个基因中形成单倍型，并检查这一重要途径中多个基因的相互作用。为了调查这些关联，我们将采用两个阶段的方法。在第一阶段，我们将利用乳腺CFR和kConFab的现有资源，在乳腺癌女性及其未受影响的女性兄弟姐妹中进行基于家庭的关联设计，确定与乳腺癌显著相关的基因变异。在第二阶段，我们将在基于人群的病例对照设计中验证从基于家庭的设计中确定的相关性。我们的具体目标是：目的1.确定IGF信号转导相关基因中的单核苷酸多态(SNPs)，并确定单倍型标记SNPs用于基因分型，从而最大限度地获取遗传信息。目的2.对高加索人乳腺癌同胞中Aim 1基因的SNPs进行分型。在3576对不和谐的同胞对(2126个同胞)中，有2420名患者(病例)和3118名未受影响的患者(对照)。目的3.探讨胰岛素样生长因子信号转导相关基因的单倍型和SNPs与乳腺癌发病风险和确诊年龄的关系。我们将分析主效应、基因x基因互作和基因x环境互作。流行病学因素将包括更年期状态、体重指数、体力活动和外源性激素使用。目的4.利用1900例高加索人群病例和1900名年龄匹配的对照，验证SNPs和单倍型与目标3中确定的乳腺癌风险的显著相关性。我们将进一步探索非裔美国人、亚裔美国人和西班牙裔不和谐同胞中有效的SNPs和单倍型。这项研究将解决乳腺癌研究中一个关键但在很大程度上被低估的领域--在调控细胞增殖的核心途径中识别遗传风险因素，细胞增殖是乳腺癌发生和发展的基础过程。这些结果将提供信息，以便更准确地评估妇女患乳腺癌的风险，并针对可能从预防战略中受益的妇女。目前，化疗针对的是IGF途径，这项研究的结果可能会提供进一步的靶点，并有助于确定哪些妇女可以从这些新药中特别受益。

DESCRIPTION (provided by applicant): Breast cancer is the most common cancer among women, with significant morbidity and mortality. We hypothesize that variation in genes involved in insulin-like growth factor (IGF) signaling play a key role in breast cancer etiology. The IGF pathway regulates cell growth, and as uncontrolled cell growth is a hallmark of cancer, this pathway is a key component. We propose a comprehensive analysis of genes involved in IGF signaling through an approach that combines multiple variants in a single gene to form haplotypes and examines interactions of multiple genes in this important pathway. To investigate these associations, we will employ a two-stage approach. In the first stage, we will identify genetic variants significantly associated with breast cancer in a family-based association design of women with breast cancer and their unaffected female siblings, using existing resources of the Breast CFR and the kConFab. In the second stage, we will validate associations identified from the family-based design in a case-control design of population-based cases and controls. Our specific aims are: Aim 1 .To identify Single Nucleotide Polymorphisms (SNPs) in genes involved in IGF signaling and determine the haplotype tagging SNPs for genotyping that will maximize genetic information. Aim 2.To genotype SNPs selected in Aim 1 in the Caucasian breast cancer sibships. There are 2420 affecteds (cases) and 3118 unaffecteds (controls) in 3576 discordant sibling pairs (2126 sibships). Aim 3. To evaluate the association of haplotypes and SNPs in genes involved in IGF signaling and risk of breast cancer and age at diagnosis. We will analyze main effects, gene x gene interactions and gene x environment interactions. Epidemiological factors will include menopausal status, body mass index, physical activity, and exogenous hormone use. Aim 4.To validate significant associations of SNPs and haplotypes with breast cancer risk identified in Aim 3 using a set of 1900 Caucasian population-based cases and 1900 age-matched controls. We will further explore validated SNPs and haplotypes in African-American, Asian-American, and Hispanic discordant sibships. This study will address a critical and yet largely under-evaluated area in breast cancer research - the identification of genetic risk factors in a pathway central to the regulation of cell proliferation, a process underlying the development and progression of breast cancer. These results will provide information to more accurately assess breast cancer risk in women and to target women who could benefit from prevention strategies. Currently, chemotherapies are being directed to the IGF pathway and the results of this study could provide further targets, as well as assist in identifying the group of women who could particularly benefit from these new drugs.