Abstract
Fibroblast growth factor receptor 2 (FGFR2) is a member of a receptor tyrosine kinase gene superfamily, involved in cell growth, invasiveness, motility, and angiogenesis, which has attracted considerable attention as a candidate gene for breast cancer (BC) since it was first identified through genome-wide association approach. In the past few years, the relationship between FGFR2 and BC has been reported in various ethnic groups; however, these studies have yielded contradictory results. 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. Overall, significantly increased BC risk was associated with these polymorphisms when all studies were pooled into the meta-analysis. In addition, our data indicate that FGFR2 is involved in BC susceptibility and confer its effect primarily in estrogen receptor-positive and progesterone receptor-positive tumors. When stratified by ethnicity, significantly increased risks were found in Caucasian and East Asian populations. However, no significant associations were detected among African descent populations. There was strong evidence of heterogeneity (P < 0.05), which largely disappeared after stratification by ethnicity. This meta-analysis demonstrated that FGFR2 polymorphism is a risk factor associated with increased BC susceptibility, but these associations vary in different ethnic populations.
Similar content being viewed by others
References
Collaborative Group on Hormonal Factors in Breast Cancer (2001) Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58 209 women with breast cancer and 101,986 women without the disease. Lancet 358:1389–1399
Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J et al (2000) Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343:78–85
Lux MP, Fasching PA, Beckmann MW (2006) Hereditary breast and ovarian cancer: review and future perspectives. J Mol Med 84:16–28
Pharoah PD, Antoniou A, Bobrow M, Zimmern RL, Easton DF, Ponder BA (2002) Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31:33–36
Grose R, Dickson C (2005) Fibroblast growth factor signaling in tumorigenesis. Cytokine Growth Factor Rev 16:179–186
Moffa AB, Ethier SP (2007) Differential signal transduction of alternatively spliced FGFR2 variants expressed in human mammary epithelial cells. J Cell Physiol 210:720–731
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188
Woolf B (1955) On estimating the relation between blood group and disease. Ann Hum Genet 19:251–253
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634
Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101
Butt S, Harlid S, Borgquist S, Ivarsson M, Landberg G et al (2012) Genetic predisposition, parity, age at first childbirth and risk for breast cancer. BMC Res Notes 5:414
Shan J, Mahfoudh W, Dsouza SP, Hassen E, Bouaouina N et al (2012) Genome-wide association studies (GWAS) breast cancer susceptibility loci in Arabs: susceptibility and prognostic implications in Tunisians. Breast Cancer Res Treat 135:715–724
Fu F, Wang C, Huang M, Song C, Lin S et al (2012) Polymorphisms in second intron of the FGFR2 gene are associated with the risk of early-onset breast cancer in Chinese Han women. Tohoku J Exp Med 226:221–229
Ma YP, van Leeuwen FE, Cooke R, Broeks A, Enciso-Mora V et al (2012) FGFR2 genotype and risk of radiation-associated breast cancer in Hodgkin lymphoma. Blood 119:1029–1031
Huo D, Zheng Y, Ogundiran TO, Adebamowo C, Nathanson KL et al (2012) Evaluation of 19 susceptibility loci of breast cancer in women of African ancestry. Carcinogenesis 33:835–840
Chen F, Lv M, Xue Y, Zhou J, Hu F et al (2012) Genetic variants of fibroblast growth factor receptor 2 (FGFR2) are associated with breast cancer risk in Chinese women of the Han nationality. Immunogenetics 64:71–76
Campa D, Kaaks R, Le Marchand L, Haiman CA, Travis RC et al (2011) Interactions between genetic variants and breast cancer risk factors in the breast and prostate cancer cohort consortium. J Natl Cancer Inst 103:1252–1263
Fletcher O, Johnson N, Orr N, Hosking FJ, Gibson LJ et al (2011) Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study. J Natl Cancer Inst 103:425–435
Higginbotham KS, Breyer JP, Bradley KM, Schuyler PA, Plummer WD Jr et al (2011) A multistage association study identifies a breast cancer genetic locus at NCOA7. Cancer Res 71:3881–3888
Slattery ML, Baumgartner KB, Giuliano AR, Byers T, Herrick JS et al (2011) Replication of five GWAS-identified loci and breast cancer risk among Hispanic and non-Hispanic white women living in the Southwestern United States. Breast Cancer Res Treat 129:531–539
Teraoka SN, Bernstein JL, Reiner AS, Haile RW, Bernstein L et al (2011) Single nucleotide polymorphisms associated with risk for contralateral breast cancer in the Women’s Environment, Cancer, and Radiation Epidemiology (WECARE) Study. Breast Cancer Res 13:R114
Han W, Woo JH, Yu JH, Lee MJ, Moon HG et al (2011) Common genetic variants associated with breast cancer in Korean women and differential susceptibility according to intrinsic subtype. Cancer Epidemiol Biomarkers Prev 20:793–798
Sueta A, Ito H, Kawase T, Hirose K, Hosono S et al (2011) A genetic risk predictor for breast cancer using a combination of low-penetrance polymorphisms in a Japanese population. Breast Cancer Res Treat 132:711–721
Marian C, Ochs-Balcom HM, Nie J, Kallakury BV, Ambrosone CB et al (2011) FGFR2 intronic SNPs and breast cancer risk: associations with tumor characteristics and interactions with exogenous exposures and other known breast cancer risk factors. Int J Cancer 129:702–712
Chen XH, Li XQ, Chen Y, Feng YM (2011) Risk of aggressive breast cancer in women of Han nationality carrying TGFB1 rs1982073 C allele and FGFR2 rs1219648 G allele in North China. Breast Cancer Res Treat 125:575–582
Gaudet MM, Kirchhoff T, Green T, Vijai J, Korn JM et al (2010) Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. PLoS Genet 6:e1001183
Travis RC, Reeves GK, Green J, Bull D, Tipper SJ et al (2010) Gene-environment interactions in 7610 women with breast cancer: prospective evidence from the Million Women Study. Lancet 375:2143–2151
Tamimi RM, Lagiou P, Czene K, Liu J, Ekbom A et al (2010) Birth weight, breast cancer susceptibility loci, and breast cancer risk. Cancer Causes Control 21:689–696
Long J, Shu XO, Cai Q, Gao YT, Zheng Y et al (2010) Evaluation of breast cancer susceptibility loci in Chinese women. Cancer Epidemiol Biomarkers Prev 19:2357–2365
Gorodnova TV, Kuligina E, Yanus GA, Katanugina AS, Abysheva SN et al (2010) Distribution of FGFR2, TNRC9, MAP3K1, LSP1, and 8q24 alleles in genetically enriched breast cancer patients versus elderly tumor-free women. Cancer Genet Cytogenet 199:69–72
Milne RL, Gaudet MM, Spurdle AB, Fasching PA, Couch FJ et al (2010) Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case–control study. Breast Cancer Res 12:R110
Ren L, Zhang B, Cao XC, Chen Y, Ge J (2010) Association of FGFR2 gene polymorphism with estrogen receptor positive breast cancer detected by fluorescent quantitative PCR. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 27:445–448
Barnholtz-Sloan JS, Shetty PB, Guan X, Nyante SJ, Luo J et al (2010) FGFR2 and other loci identified in genome-wide association studies are associated with breast cancer in African-American and younger women. Carcinogenesis 31:1417–1423
Rebbeck TR, DeMichele A, Tran TV, Panossian S, Bunin GR et al (2009) Hormone-dependent effects of FGFR2 and MAP3K1 in breast cancer susceptibility in a population-based sample of post-menopausal African-American and European-American women. Carcinogenesis 30:269–274
Liu M, Shan K, He Y et al (2009) The relationship between two FGFR2 polymorphisms and breast cancer. Zhong Guo Zhong Liu Lin Chuang 36:413–416
Prentice RL, Huang Y, Hinds DA, Peters U, Pettinger M et al (2009) Variation in the FGFR2 gene and the effects of postmenopausal hormone therapy on invasive breast cancer. Cancer Epidemiol Biomarkers Prev 18:3079–3085
Kawase T, Matsuo K, Suzuki T, Hiraki A, Watanabe M et al (2009) FGFR2 intronic polymorphisms interact with reproductive risk factors of breast cancer: results of a case control study in Japan. Int J Cancer 125:1946–1952
Udler MS, Meyer KB, Pooley KA, Karlins E, Struewing JP et al (2009) FGFR2 variants and breast cancer risk: fine-scale mapping using African American studies and analysis of chromatin conformation. Hum Mol Genet 18:1692–1703
Zheng W, Cai Q, Signorello LB, Long J, Hargreaves MK et al (2009) Evaluation of 11 breast cancer susceptibility loci in African-American women. Cancer Epidemiol Biomarkers Prev 18:2761–2764
McInerney N, Colleran G, Rowan A, Walther A, Barclay E et al (2009) Low penetrance breast cancer predisposition SNPs are site specific. Breast Cancer Res Treat 117:151–159
Boyarskikh UA, Zarubina NA, Biltueva JA, Sinkina TV, Voronina EN et al (2009) Association of FGFR2 gene polymorphisms with the risk of breast cancer in population of West Siberia. Eur J Hum Genet 17:1688–1691
Hemminki K, Muller-Myhsok B, Lichtner P, Engel C, Chen B et al (2010) Low-risk variants FGFR2, TNRC9 and LSP1 in German familial breast cancer patients. Int J Cancer 126:2858–2862
Garcia-Closas M, Hall P, Nevanlinna H, Pooley K, Morrison J et al (2008) Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet 4:e1000054
Liang J, Chen P, Hu Z, Zhou X, Chen L et al (2008) Genetic variants in fibroblast growth factor receptor 2 (FGFR2) contribute to susceptibility of breast cancer in Chinese women. Carcinogenesis 29:2341–2346
Stacey SN, Manolescu A, Sulem P, Thorlacius S, Gudjonsson SA et al (2008) Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 40:703–706
Antoniou AC, Spurdle AB, Sinilnikova OM, Healey S, Pooley KA et al (2008) Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet 82:937–948
Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M et al (2007) A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39:870–874
Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108
Collaborative Group on Hormonal Factors in Breast Cancer (2002) Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 360:187–195
Tamaru N, Hishikawa Y, Ejima K, Nagasue N, Inoue S et al (2004) Estrogen receptor-associated expression of keratinocyte growth factor and its possible role in the inhibition of apoptosis in human breast cancer. Lab Invest 84:1460–1471
Tozlu S, Girault I, Vacher S, Vendrell J, Andrieu C et al (2006) Identification of novel genes that co-cluster with estrogen receptor alpha in breast tumor biopsy specimens, using a large-scale real-time reverse transcription-PCR approach. Endocr Relat Cancer 13:1109–1120
Allred DC, Brown P, Medina D (2004) The origins of estrogen receptor alpha-positive and estrogen receptor alpha-negative human breast cancer. Breast Cancer Res 6:240–245
Qiu M, Olsen A, Faivre E, Horwitz KB, Lange CA (2003) Mitogen-activated protein kinase regulates nuclear association of human progesterone receptors. Mol Endocrinol l17:628–642
Giulianelli S, Cerliani JP, Lamb CA, Fabris VT, Bottino MC et al (2008) Carcinoma-associated fibroblasts activate progesterone receptors and induce hormone independent mammary tumor growth: a role for the FGF-2/FGFR-2 axis. Int J Cancer 123:2518–2531
Jia C, Cai Y, Ma Y, Fu D (2010) Quantitative assessment of the effect of FGFR2 gene polymorphism on the risk of breast cancer. Breast Cancer Res Treat 124:521–528
Conflict of interest
We declare that we have no conflict of interest.
Author information
Authors and Affiliations
Corresponding authors
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Wang, H., Yang, Z. & Zhang, H. Assessing interactions between the associations of fibroblast growth factor receptor 2 common genetic variants and hormone receptor status with breast cancer risk. Breast Cancer Res Treat 137, 511–522 (2013). https://doi.org/10.1007/s10549-012-2343-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-012-2343-7