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）信号传导的基因变异在乳腺癌病因学中起关键作用。IGF通路调节细胞生长，由于不受控制的细胞生长是癌症的一个标志，因此该通路是一个关键组成部分。我们建议通过将单个基因中的多个变体结合形成单倍型的方法，对参与IGF信号传导的基因进行全面分析，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，我们将利用乳腺癌CFR和kConFab的现有资源，在基于家族的乳腺癌女性及其未受影响的女性兄弟姐妹的关联设计中，确定与乳腺癌显著相关的遗传变异。在第二阶段，我们将在基于人群的病例和对照的病例对照设计中验证从基于家庭的设计中确定的关联。我们的具体目标是：目标1。鉴定参与IGF信号传递的基因中的单核苷酸多态性（snp），并确定单倍型标记snp用于基因分型，从而最大化遗传信息。目标2。对高加索乳腺癌兄弟姐妹中Aim 1中选择的snp进行基因分型。在3576对不一致的兄弟姐妹（2126对姐妹）中，有2420例受影响（病例）和3118例未受影响（对照）。目标3。评估与IGF信号相关的基因的单倍型和snp与乳腺癌风险和诊断年龄的关系。我们将分析主效应、基因x基因相互作用和基因x环境相互作用。流行病学因素包括绝经状态、体重指数、体力活动和外源性激素的使用。目标4。通过一组1900例基于高加索人群的病例和1900例年龄匹配的对照，验证在Aim 3中确定的snp和单倍型与乳腺癌风险的显著关联。我们将进一步探索非裔美国人、亚裔美国人和西班牙裔不一致兄弟姐妹中已验证的snp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——确定细胞增殖调控通路中的遗传风险因素，这是乳腺癌发生和发展的一个潜在过程。这些结果将提供信息，以更准确地评估妇女患乳腺癌的风险，并针对可能从预防策略中受益的妇女。目前，化疗都是针对IGF通路的，这项研究的结果可以提供进一步的靶点，并有助于确定能够从这些新药中受益的女性群体。

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.