Abstract A74: Association between FGFR2 SNPs, breast cancer risk factors, and clinical and pathological features of breast tumors in the Western New York Exposures and Breast Cancer (WEB) study

Abstract

Abstract A74 Previous observations indicate that FGFR2 is involved in estrogen-related breast carcinogenesis and is amplified and overexpressed in breast cancer, the levels of expression being higher in ER-positive than ER-negative cell lines and tumors. In two recent genome-wide association studies (GWAS), SNPs in intron 2 of FGFR2 were associated with breast cancer risk with ORs of about 1.6. To date, 2 studies have found stronger associations of FGFR2 SNPs with ER+, PR+, lower grade, node positive breast tumors and one study found a positive correlation with family history of breast cancer. Here we investigated 4 SNPs (rs11200014, rs1219648, rs2420946, rs2981579) in intron 2 of FGFR2 in order to replicate the GWAS findings and assess the association with breast cancer risk factors, and clinical and pathological features of breast tumors in a population-based case-control study, the Western New York Exposures and Breast Cancer study. Genomic DNA and SNP genotyping was performed by allelic discrimination real time PCR for 991 cases and 1698 controls. Demographics, reproductive history, lifetime alcohol consumption and smoking were queried by interview. Clinical and pathological characteristics of 803 tumors were abstracted from hospital records. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). We confirmed the overall association of variant alleles of FGFR2 intron 2 SNPs with breast cancer risk (OR 1.52, CI 1.20-1.94) as well as previously reported associations with ER+ (1.36, 1.11-1.67), PR+ (1.47, 1.19-1.83), lower grade tumors (1.57, 1.10-2.25) and family history of breast cancer (2.00, 1.50-2.67). We also found an association with negative node tumors in our sample set (1.29, 1.05-1.58). Additionally, we observed associations with Ki67- (1.33, 1.16-1.52), lower stage (1.42, 1.21-1.66) and smaller size (1.39, 1.21-1.59) tumors. Also, all four SNPs were associated with older age (1.96, 1.47-2.61), higher education (1.51, 1.17-1.94), higher postmenopausal BMI (1.53, 1.15-2.05), younger age at menarche (1.48, 1.05-2.08), lower number of births (2.55, 1.77-3.68), and previous benign breast disease (2.28, 1.76-2.95). Marginal association with alcohol drinking (OR 1.46, CI 0.92-2.32) and significant association with smoking status (OR 1.94, 1.37-2.75) were found. This is the first study that comprehensively investigates interactions of FGFR2 SNPs with breast cancer risk factors, and clinical and pathological features of breast tumors in relation to breast cancer risk. Our results support the hypothesis that FGFR2 is involved in estrogen-related breast carcinogenesis, suggested by the association with ER+ tumors and reproductive history. Moreover, lifestyle exposures like alcohol and smoking seem to modulate the association of FGFR2 SNPs and breast cancer, perhaps through estrogen related mechanisms as well, although further studies are needed to elucidate these mechanisms. Supported by the following grants: DAMD-17-03-1-0446, DAMD-17-00-1-0417 and NCI-RO1CA92040 Marian C was supported by an AVON-AACR International Scholar in Breast Cancer Research Award Citation Information: Cancer Prev Res 2008;1(7 Suppl):A74.