The IGF Signaling Pathway and Breast Cancer Risk

IGF 信号通路与乳腺癌风险

基本信息

批准号：
7777345
负责人：
Susan L. Neuhausen
金额：
$ 51.85万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-12 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7777345
关键词：
Address Affect African American Age Area Asian Americans Biological Models Body mass index CTSD gene Cancer Etiology Caucasians Caucasoid Race Cell Proliferation Regulation Codon Nucleotides DNA Resequencing Data Development Diagnosis Diagnostic Neoplasm Staging Disease Disease Progression ESR1 gene ESR2 gene Environment Epidemiologic Studies Epidemiological Factors Estrogens Etiology Exogenous Hormone Therapy Family Female Foundations Functional RNA Genes Genetic Genetic Epistasis Genetic Variation Genotype Haplotypes Hereditary Breast Carcinoma Hispanics IGF1 gene IGF1R gene IGF2 gene IGF2R gene IGFBP1 gene IGFBP2 gene IGFBP3 gene IGFBP4 gene IGFBP5 gene IGFBP6 gene INSR gene IRS1 gene IRS2 gene Insulin-Like Growth Factor I Introns KLK3 gene Linkage Disequilibrium MMP3 gene Malignant Neoplasms Menopausal Status Modeling Morbidity - disease rate Pathway interactions Pharmaceutical Preparations Physical activity Play Premenopause Prevention Prevention strategy Process Research Resources Risk Risk Assessment Role SHBG gene SHC1 gene Serum Siblings Signal Pathway Signal Transduction Single Nucleotide Polymorphism Sister Somatomedins Staging Tumor stage Variant Woman Women&apos s Group anticancer research base breast cancer family registry cancer risk case control cell growth chemotherapy design genetic risk factor genetic variant malignant breast neoplasm mortality population based secondary outcome treatment strategy uncontrolled cell growth validation studies

项目摘要

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.

描述（由申请人提供）：乳腺癌是女性中最常见的癌症，发病率和死亡率很高。我们假设与胰岛素样生长因子（IGF）信号相关的基因变异在乳腺癌病因学中发挥着关键作用。 IGF 途径调节细胞生长，由于不受控制的细胞生长是癌症的一个标志，因此该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 信号传导的基因进行全面分析，该方法将单个基因中的多个变体组合形成单倍型，并检查该重要途径中多个基因的相互作用。为了研究这些关联，我们将采用两阶段方法。在第一阶段，我们将利用乳腺癌 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的基于家庭的关联设计中识别与乳腺癌显着相关的遗传变异。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 信号传导的基因中的单核苷酸多态性 (SNP)，并确定用于基因分型的单倍型标记 SNP，从而最大限度地利用遗传信息。目标 2. 对目标 1 中选择的高加索乳腺癌同胞中的 SNP 进行基因分型。在 3576 个不一致的兄弟姐妹对（2126 个兄弟姐妹）中，有 2420 名受影响者（病例）和 3118 名未受影响者（对照）。目标 3. 评估参与 IGF 信号传导的基因中的单倍型和 SNP 与乳腺癌风险和诊断年龄之间的关联。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。流行病学因素包括更年期状况、体重指数、体力活动和外源性激素的使用。目标 4. 使用一组 1900 个基于白人群体的病例和 1900 个年龄匹配的对照来验证 SNP 和单倍型与目标 3 中确定的乳腺癌风险的显着关联。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同胞中经过验证的 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——识别细胞增殖调节的核心途径中的遗传风险因素，细胞增殖是乳腺癌发生和进展的基础过程。这些结果将为更准确地评估女性乳腺癌风险提供信息，并针对可以从预防策略中受益的女性。目前，化疗正在针对 IGF 途径，这项研究的结果可以提供进一步的目标，并帮助确定哪些女性群体可以特别受益于这些新药。