Genetic variation in the insulin, insulin-like growth factor, growth hormone, and leptin pathways in relation to breast cancer in African-American women: the AMBER consortium.

Edward A Ruiz-Narváez,Melissa A Troester,Kathryn L Lunetta,Julie R Palmer,Jeannette T Bensen,Song Yao,Ting-Yuan David Cheng,Christine B Ambrosone,Stephen Haddad,Lynn Rosenberg,Elisa V Bandera,Christopher A Haiman,Chi-Chen Hong

doi:10.1038/npjbcancer.2016.34

Abstract

The insulin/insulin-like growth factor (IGF) system and related pathways such as growth hormone, and leptin signaling have a key role in cancer development. It is unclear how germline variation in these pathways affects breast cancer risk. We conducted gene-based analyses of 184 genes in the insulin/IGF, growth hormone, and leptin pathways to identify genetic variation associated with risk of breast cancer overall, and for estrogen receptor (ER) subtypes. Tag single-nucleotide polymorphisms (SNPs) for each gene were selected and genotyped on a customized Illumina SNP array. Imputation was carried out using 1000 Genomes haplotypes. The analysis included 91,627 SNPs genotyped or imputed in 3,663 breast cancer cases, (1,983 ER-positive and 1,098 ER-negative) and 4,687 controls from the African American Breast Cancer Epidemiology and Risk consortium, a collaborative project of four large studies of breast cancer in African-American women (Carolina Breast Cancer Study, Black Women's Health Study, Women's Circle of Health Study, and Multiethnic Cohort). We used a multi-locus adaptive joint test to determine the association of each gene with overall breast cancer and ER subtypes. The most significant gene associations (P⩽0.01) were BAIAP2 and CALM2 for overall breast cancer; BAIAP2 and CSNK2A1 for ER+ breast cancer; and BRAF, BAD, and MAPK3 for ER− breast cancer. The association of BAD with ER− breast cancer was explained by a two-SNP risk model; all other associations were best explained by one-SNP risk models. In total, six genes and seven SNPs had suggestive associations with overall breast cancer or ER subtypes in African-American women.

Highlights

A growing body of evidence shows that the insulin signaling system has a key role in cancer development and progression
A pooled analysis of 17 prospective studies found that the association of circulating insulin-like growth factor (IGF)-1 with breast cancer was not modified by circulating levels of IGF-binding protein 3 (IGFBP-3)
BAIAP2 and CSNK2A1 were associated with estrogen receptor (ER)+ breast cancer, and BRAF, BAD and MAPK3 were associated with ER − breast cancer

Summary

Introduction

A growing body of evidence shows that the insulin signaling system has a key role in cancer development and progression. A condition leading to insulin resistance and hyperinsulinemia, is a recognized risk factor for postmenopausal breast cancer.[1,2,3] the association between body weight and breast cancer is mediated in part by higher levels of estrogen in overweight women, insulin levels seems to have a larger mediating role.[4] Recent results show that high levels of insulin levels rather than adiposity is the relevant risk factor in relation to breast cancer risk. Overweight women with low insulin levels have no elevated risk of breast cancer compared with normal-weight women with low insulin levels, and women with high insulin levels have elevated risk of breast cancer irrespective of their body weight.[5]. IGF-1 and insulin share downstream signaling pathways. Circulating levels of IGF-1 have been found to be positively associated with breast cancer risk.[6,7,8,9] A pooled analysis of 17 prospective studies found that the association of circulating IGF-1 with breast cancer was not modified by circulating levels of IGF-binding protein 3 (IGFBP-3)

Methods

Results

Conclusion