Abstract 2790: Gene-based analysis of the fibroblast growth factor receptor signaling pathway identifies an association of the FGF1 gene with risk of estrogen receptor-negative breast cancer: The AMBER consortium
Authors: Ruiz-Narvaez Edward A. , Haddad Stephen , Haiman Christopher A. , Yao Song , Sucheston-Campbell Lara E. , Bensen Jeanette T. , Lunetta Kathryn L. , Olshan Andrew F. , Ambrosone Christine B. , Palmer Julie R. 
Published: August 2015

Fibroblast growth factors (FGFs) and their receptors (FGFRs) play key roles in several cellular processes such as differentiation, proliferation, migration and survival. Deregulation of the FGFR signaling pathway has been associated with human cancer including breast cancer, and GWAS-identified polymorphisms in the FGFR2 gene have been associated with risk of both overall and estrogen receptor (ER)-positive breast cancer. We conducted gene-based analysis in 26 genes in the FGFR signaling pathway to identify genes carrying genetic variation affecting risk of breast cancer and the specific ER subtypes. Tagging single nucleotide polymorphisms (SNPs) at ±10 kb of each gene were selected and genotyped in a customized Illumina Exome Array. Imputation was carried out using 1000 Genomes haplotypes. The analysis included 9,264 SNPs in 3,663 breast cancer cases (including 1,983 estrogen receptor-positive (ER+), and 1,098 estrogen receptor-negative (ER-)) and 4,687 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) consortium, a collaborative study of four of the largest studies of breast cancer in African American women (Carolina Breast Cancer Study, Black Women's Health Study, Women's Circle of Health Study, and Multi-Ethnic Cohort). We used the adaptive rank-truncated product (ARTP) method implemented in R-package PIGE to determine the association of each gene in the FGFR signaling pathway with overall breast cancer, and ER subtypes. Analyses were adjusted for principal components of genetic variation to control for population stratification, age, geographic region of residence, study, and source of DNA. An alpha level of 0.002 ( = 0.05/26 genes) was used to determine statistical significance at the gene-wide level. After adjustment for multiple testing the FGF1 gene was associated with risk of ER-negative breast cancer (p = 0.001). The FGF1 gene codes for the fibroblast growth factor 1. Genetic variation in this gene has been reported to be associated with risk of ovarian cancer and with breast cancer survival. As expected, the FGFR2 gene was associated with risk of overall breast cancer (p = 0.001) and ER-positive breast cancer (p = 0.002). In summary, we found that the FGF1 gene affects risk of ER-negative breast cancer in African American women, and we confirmed the association of the FGFR2 gene with risk of overall and ER-positive breast cancer. These results highlight the importance of the FGFR signaling pathway in the pathogenesis of breast cancer, and suggest that different genes in the same pathway may be associated with different ER breast cancer subtypes.

Citation Format: Edward A. Ruiz-Narvaez, Stephen Haddad, Christopher A. Haiman, Song Yao, Lara E. Sucheston-Campbell, Jeanette T. Bensen, Kathryn L. Lunetta, Andrew F. Olshan, Christine B. Ambrosone, Julie R. Palmer. Gene-based analysis of the fibroblast growth factor receptor signaling pathway identifies an association of the FGF1 gene with risk of estrogen receptor-negative breast cancer: The AMBER consortium. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2790. doi:10.1158/1538-7445.AM2015-2790