FGFR2 intronic polymorphisms interact with reproductive risk factors of breast cancer: Results of a case control study in Japan

Abstract

Recently, 2 genome-wide association studies demonstrated that single nucleotide polymorphisms (SNPs) of the fibroblast growth factor receptor 2 (FGFR2) gene at intron 2 are significantly associated with the risk of female breast cancer. As the next step, it is necessary to evaluate the interaction between these SNPs and known risk factors of breast cancer because such an evaluation could elucidate mechanisms of carcinogenesis and lead to preventive advances. We conducted a case-control study of 456 newly and histologically diagnosed breast cancer cases and 912 age-and menopausal status-matched noncancer controls. The impact of 5 FGFR2 intronic SNPs on the risk of breast cancer and the interactions between these SNPs and various known risk factors of breast cancer were evaluated in both pre and postmenopausal women. We observed a statistically significant association between 4 SNPs and breast cancer risk and these 4 SNPs were in strong linkage disequilibrium in the Japanese population. rs2420946 was associated with a population-attributable risk of 17.7%. We found that FGFR2 polymorphisms interact with family history of breast cancer (interaction p 5 0.003) and reproductive risk factors, namely, age at menarche (interaction p 5 0.019) and parity (interaction p 5 0.026). Of note, a significant association between body mass index (BMI) 25 and FGFR2 polymorphism was observed among postmenopausal women (trend p 5 0.012), but not among premenopausal women. In contrast, BMI < 25 had no significant association with this polymorphism regardless of menopausal status. These findings suggest that FGFR2 intronic SNPs affect the reproductive hormone-related pathway and contribute to the development of female breast cancer in the Japanese population. ' UICCKey words: breast cancer; reproductive hormone; FGFR2 intronic polymorphisms Breast cancer ranks first among cancers affecting women worldwide. 1 The incidence rate of breast cancer in the Japanese population is generally lower than that in Caucasian populations and higher than that in other Asian populations. 2 In the Japanese population 3 and in other Asian populations, 4 the incidence of breast cancer increases rapidly until menopause, and then it reaches a plateau or decreases.Recently, 2 large genome-wide association studies demonstrated that intronic single nucleotide polymorphisms (SNPs) of the fibroblast growth factor receptor 2 (FGFR2) gene are significantly associated with the risk of female breast cancer, 5,6 although 1 study was conducted in sporadic postmenopausal women and the other was conducted in women who had a strong family history of breast cancer in the first stage of the study. Subsequently, the association of FGFR2 polymorphisms with breast cancer was reported in Jewish and Arab Israeli populations, 7 Chinese population 8 and European-American but not African-American population. 9 Several other studies indicated that FGFR2 is associated with carcinogenesis of some types of cancer; that is, overexpression or missense mutation of FGFR2 occurs in breas...

Current evidence on the relationship between three polymorphisms in the FGFR2 gene and breast cancer risk: a meta-analysis

“…A total of six publications [11][12][13][14][15][16] met the inclusion criteria and were used in this meta-analysis. The genome-wide association study (GWAS) of Hunter et al [11] consisted of NHS (Nurses' Health Study) study, NHS-2 study, ACS study, and PLCO study.…”

“…Aberrant expression of alternatively spliced isoforms of FGFR2 transforms breast cancer cells by sustained signal transduction [4][5][6][7][8][9]. In recent years, some original publications [10][11][12][13][14][15][16] have reported the role of FGFR2 polymorphism in breast cancer risk. The association is restricted to single nucleotide polymorphisms (SNPs) in the linkage disequilibrium block covering intron 2, in which three polymorphic variants, rs1219648 (A [ G), rs2420946 (C [ T), and rs2981582 (C [ T), have been the research focus in scientific community and have drawn increasing attention.…”

A genetic risk predictor for breast cancer using a combination of low-penetrance polymorphisms in a Japanese population

“…In addition, we calculated the PAF to evaluate the extent to which this genetic risk score could be attributed to the proportion of disease risk in a population. Several papers have described a PAF for only one SNP in the FGFR2 gene of about 16-18% [6,34]. With regard to the established risk factors of breast cancer, PAFs for age at menarche and parity were 18.8% and 13.3%, respectively [35].…”

Polymorphisms in Second Intron of the FGFR2 Gene Are Associated with the Risk of Early-Onset Breast Cancer in Chinese Han Women

“…a significant association has been demonstrated between the presence of the FGFR2 rs11200014 SNP and the incidence of breast cancer in European Caucasians (Hunter et al 2007), Ashkenazi and Sephardi Jews (Raskin et al 2008), and african-americans (Barnholtz-Sloan et al 2010). However, there appears to be no statistical correlation between this SNP and breast cancer risk in the Japanese, neither in premenopausal nor in postmenopausal women (Kawase et al 2009). This may be due in part to the quite different LD patterns of European and Asian populations.…”