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A Comprehensive Genomic Approach to Characterize the Role of Genetic Variation in IGF Receptor Genes in Relation to Breast Cancer Risk: The Multiethnic Cohort
The Insulin-like Growth Factor (IGF) system has an established role in cellular growth, and accumulating evidence support the involvement of the IGF system in breast cancer development and progression. IGFs are mitogens that play a critical role in cell proliferation and apoptosis. The Insulin-like Growth Factor-1 Receptor (IGF1R) and Insulin-like Growth Factor-2 Receptor (IGF2R) genes are of particular interest given their role in mediating IGF activity; it has yet to be determined whether genetic variations in these genes contribute to breast cancer risk. With recent innovations in genomic technology, large scale studies have advanced our understanding of human genetic variation and have lead to the development of promising approaches to evaluate the inherited contribution of candidate genes to breast cancer susceptibility.
The hypothesis of this proposal is that common genetic variations in IGF1R and IGF2R are associated with breast cancer risk. Our specific aims are:
1. To characterize the haplotype block structures and identify a set of haplotype-tagging single nucleotide polymorphisms (htSNPs) that capture the common haplotype diversity of IGF1R and IGF2R among African-American, Native Hawaiian, Japanese, Latina, and white women.
2. To examine the association between common haplotypes of IGF1R and IGF2R and breast cancer risk.
3. To evaluate gene-gene haplotype interactions between the IGF1R and IGF2R genes and previously characterized haplotypes of IGF-I, IGFBP1, and IGFBP3.
A haplotype-based approach using linkage disequilibrium mapping will be used to identify chromosomal regions of IGF1R and IGF2R that may harbor putative disease-associated variants. A high density of SNPs spanning IGF1R and IGF2R will be genotyped using high-throughput genotyping methods in a multiethnic panel of 350 controls. We will estimate the common haplotypes and identify htSNPs that predict the common haplotypes in each population. Associations between common haplotypes of IGF1R and IGF2R and breast cancer risk will be examined in a case-control study (1715 cases/2502 controls) within a multiethnic cohort study.
The overall goal of this proposal is to assess the genetic contribution of two candidate breast cancer susceptibility genes in the development of breast cancer, with a particular focus on understanding ethnic differences in risk. Such detailed knowledge may be beneficial to the development and design of therapies for breast cancer, and aid in the identification of women at greater risk of disease who may benefit from early detection and prevention strategies.
Background: Breast cancer is characterized by uncontrolled cell growth and the spread of abnormal cells. Insulin-like growth factors (IGFs) are potent stimulators of breast cell proliferation and inhibitors of cell death. Multiple lines of human and experimental evidence support the role of the IGF system in breast cancer development. As the effects of IGFs are mediated through interactions with their receptors, the Insulin-like Growth Factor-1 receptor (IGF1R) and Insulin-like Growth-Factor-2 receptor (IGF2R) are attractive genes in studying breast cancer etiology.
Objective/Aims: Our central question is whether common genetic variation in IGF1R and IGF2R genes are associated with breast cancer risk. In addition, we plan to investigate whether racial/ethnic differences in breast cancer risk among African-American, Native Hawaiian, Japanese, Latina, and white women may be related to differences in the genetic sequences of the IGF receptors.
Methods: Our study population will consist of a large multiethnic population of African-American, Native Hawaiian, Japanese, Latina, and white participants in a multiethnic cohort study. We will utilize high-throughput genotyping technology to comprehensively evaluate genetic variation in the IGF1R and IGF2R genes. We will investigate whether genetic differences in IGF1R and IGF2R are associated with breast cancer risk among 1,715 breast cancer cases and 2,502 controls.
Outcomes/Benefits: This proposal integrates a large multiethnic population-based study, cutting edge genomic resources, and a novel methodologic approach to investigate the genetic contributions of the IGF receptors to breast cancer risk. This will be the first study to extensively evaluate genetic germ-line variations in IGF1R and IGF2R as they relate to breast cancer susceptibility. In addition, our study population of African-Americans, Native Hawaiian, Japanese, Latinas, and whites provides us the ability to examine genetic differences among a diversity of racial/ethnic backgrounds.