In the validation study using Stage I of the 2,273 cases and 2,052 controls, seven GWAS-identified loci [5q11.2/MAP3K1 (rs889312 and rs16886165), 5p15.2/ROPN1L (rs1092913), 5q12/MRPS30 (rs7716600), 6q25.1/ESR1 (rs2046210 and rs3734802), 8q24.21 (rs1562430), 10q26.13/FGFR2 (rs10736303), and 16q12.1/TOX3 (rs4784227 and rs3803662)] were significantly associated with breast cancer risk in Korean women (Ptrend < 0.05).
We obtained a significant allele P value of association with AJ breast cancer in the FGFR2 region (P = 1.5 x 10(-5), odds ratio (OR) 1.26, 95% confidence interval (CI) 1.13-1.40 at rs1078806 for all phases combined).
Four SNPs mapped to 10q26.13/FGFR2 were associated with increased breast cancer risk via an additive model with per-allelic risks (95 % CI) of 1.26 (1.12-1.43) at rs1219648, 1.22 (1.07-1.38) at rs2981582, 1.21 (1.07-1.36) at rs2981579, and 1.18 (1.04-1.35) at rs11200014.
Results from the current meta-analysis indicates that three novel functional polymorphisms (rs11200014, rs2981579, and rs2981578) in the promoter of FGFR2 gene are associated with breast cancer susceptibility and might be a potential biomarkers for breast cancer risk.
To investigate this inconsistency, we performed a meta-analysis of 37 studies involving a total of 288,142 subjects for rs2981582, rs1219648, and rs2420946 polymorphism of the FGFR2 gene to evaluate the effect of FGFR2 on genetic susceptibility for BC.
FGFR2 rs1219648 and rs2981582 genotypes were significantly associated with breast cancer</span> in EA only in estrogen receptor-positive (ER+), progesterone receptor-positive (PR+) and HER2/Neu-negative (HER2-) tumors.
Seven SNPs were statistically significant (P ≤ 0.05) with the risk of overall breast cancer in the same direction as previously reported: rs10069690 (5p15/TERT), rs999737 (14q24/RAD51L1), rs13387042 (2q35/TNP1), rs1219648 (10q26/FGFR2), rs8170 (19p13/BABAM1), rs17817449 (16q12/FTO), and rs13329835 (16q23/DYL2).
Three commonly studied FGFR2 polymorphisms including rs1219648 (A > G), rs2420946 (C > T), and rs2981582 (C > T) were selected to explore their association with risk of development of breast cancer by meta-analysis of published case-control studies.
The SNPs of FGFR2 rs1219648 and PI3KCA rs6443624 may contribute to the identification of breast cancer patients at risk of more aggressive disease and may be potential prognostic factors in breast cancer in a Chinese population.
This meta-analysis of case-control studies provides strong evidence that fibroblast growth factor 2 (FGFR2; rs11200014, rs2981579, and rs1219648) polymorphisms are significantly associated with the BC risk.
Genetic variation in FGFR2, identified by rs1219648, may account for a substantial fraction of breast cancer in Arab (12%), Ashkenazi (15%), and Sephardi Jewish (22%) populations.
Furthermore, there was an increased effect of BC risk between haplotype combinations of the two SNPs of FGFR2 (rs2981582 and rs1219648) in Pakistani women.
We genotyped 13 single nucleotide polymorphisms (SNPs) densely covering a 27 kb region within intron 2 of FGFR2 including two SNPs (rs2981582 and rs1219648) significantly associated with breast cancer and a total 40 tagSNPs across 150 kb of the FGFR2 gene.
Five of the 17 SNPs were significantly associated (P ≤ 0.05) with overall breast cancer in the same direction as previously reported: rs13387042 (2q35/TNP1), rs4973768 (3p24/SLC4A7), rs2046210 (6q25/ESR1), rs1219648 (10q26/FGFR2), and rs4784227 (16q12/TOX3).
The FGFR2-breast cancer association was modified by smoking status, with increased risk for former and current smokers compared to never smokers; former/current smokers carrying two copies of the rs1219648 minor allele were at highest risk with a crude OR (95% confidence interval) of 2.11 (1.52-2.92) compared to never smokers with no rs1219648 variant alleles.
There was stronger evidence of an interaction between ever use of estrogen-only HT and increasing number of rs1219648 risk alleles to increase breast cancer risk (interaction P = 0.08).
Only 5 out of 9 GWAS breast cancer loci were found to be significantly associated with breast cancer in Tunisians: The rs1219648 (G vs. A allele: OR = 1.36, P = 1 × 10(-3)) and rs2981582 (A vs. G allele: OR = 1.55, P = 3 × 10(-6)) of FGFR2 gene; the rs8051542 of the TNRC9 gene (T vs. C allele: OR = 1.40, P = 4 × 10(-4)); the rs889312 of the MAP3K1 gene (C vs. A allele: OR = 1.33, P = 3 × 10(-3)) and the rs13281615 located on 8q24 (G vs. A allele: OR = 1.21, P = 0.03).
Therefore, the SNPs of TGFB1 rs1982073 and FGFR2 rs1219648 may contribute to the identification of patients with more aggressive breast cancers among Han women in North China.