Association of FGFR2 and TOX3 Genetic Variants With the Risk of Breast Cancer in Iranian Women

Main Article Content

Mojgan Hosseini
Massoud Houshmand
Shima Froozan


Breast Cancer, FGFR2, TOX3, SNPs


Background: Breast cancer is the most common cause of cancer-related death in women worldwide. Novel genetic markers for breast cancer susceptibility have been identified in population-based studies. The aim of this study was to examine the association of two single-nucleotide polymorphisms (SNPs) of FGFR2 (rs1219648) and TOX3 (rs8051542) with the risk of breast cancer in Iranian women.
Methods: Breast cancer patients (n = 126) and healthy controls (n = 160) were genotyped for SNPs in FGFR2 (rs1219648) and TOX3 (rs8051542) using the tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Also, immunohistochemical tests for human epidermal growth factor receptor-2, estrogen receptor, and progesterone receptor were carried out on breast tumor tissues.
Results: TOX3 (rs8051542) CC (OR = 1.24; 95% CI, 0.72-0.214; P < 0.001) and FGFR2 (rs1219648) GG (OR = 62.0; 95% CI, 23.63-162.66; χ2 =132.775 ; P < 0.001) polymorphism was significantly associated with breast cancer. The association was also significant between breast cancer risk and TOX3 (rs8051542) TC and FGFR2 (rs1219648) AG variants.
Conclusion: Our findings suggested that genetic variants of FGFR2 (rs1219648 AG) and TOX3 (rs8051542 TC) can be potential candidate biomarkers for breast cancer risk.


1. DeSantis CE, Bray F, Ferlay J, Lortet-Tieulent J, Anderson BO, Jemal A. International variation in female breast cancer incidence and mortality rates. Cancer Epidemiology and Prevention Biomarkers. 2015.
2. Jazayeri SB, Saadat S, Ramezani R, Kaviani A. Incidence of primary breast cancer in Iran: Ten-year national cancer registry data report. Cancer epidemiology. 2015;39(4):519-27.
3. Jafari-Koshki T, Schmid VJ, Mahaki B. Trends of breast cancer incidence in Iran during 2004-2008: a Bayesian space-time model. Asian Pac J Cancer Prev. 2014;15(4):1557-61.
4. Barnard ME, Boeke CE, Tamimi RM. Established breast cancer risk factors and risk of intrinsic tumor subtypes. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer. 2015;1856(1):73-85.
5. Houghton LC, Ganmaa D, Rosenberg PS, Davaalkham D, Stanczyk FZ, Hoover RN, et al. Associations of breast cancer risk factors with premenopausal sex hormones in women with very low breast cancer risk. International journal of environmental research and public health. 2016;13(11):1066.
6. Michailidou K, Beesley J, Lindstrom S, Canisius S, Dennis J, Lush MJ, et al. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer. Nature genetics. 2015;47(4):373.
7. Fachal L, Dunning AM. From candidate gene studies to GWAS and post-GWAS analyses in breast cancer. Current opinion in genetics & development. 2015;30:32-41.
8. Cox DG, Curtit E, Romieu G, Fumoleau P, Rios M, Bonnefoi H, et al. GWAS in the SIGNAL/PHARE clinical cohort restricts the association between the FGFR2 locus and estrogen receptor status to HER2-negative breast cancer patients. Oncotarget. 2016;7(47):77358.
9. Zanna I, Silvestri V, Palli D, Magrini A, Rizzolo P, Saieva C, et al. Smoking and FGFR2 rs2981582 variant independently modulate male breast cancer survival: A population-based study in Tuscany, Italy. The Breast. 2018;40:85-91.
10. Han Y-J, Zhang J, Zheng Y, Huo D, Olopade OI. Genetic and epigenetic regulation of TOX3 expression in breast cancer. PloS one. 2016;11(11):e0165559.
11. Machado RA, Ferreira SB, Martins L, Ribeiro MM, Martelli DR, Coletta RD, et al. A novel heterozygous mutation in FGFR2 gene causing Pfeiffer syndrome. American Journal of Medical Genetics Part A. 2017;173(10):2838-43.
12. Jiang C, Yu S, Qian P, Guo R, Zhang R, Ao Z, et al. The breast cancer susceptibility-related polymorphisms at the TOX3/LOC643714 locus associated with lung cancer risk in a Han Chinese population. Oncotarget. 2016;7(37):59742.
13. He Y, Liu H, Chen Q, Sun X, Liu C, Shao Y. Relationship between five GWAS-identified single nucleotide polymorphisms and female breast cancer in the Chinese Han population. Tumor Biology. 2016;37(7):9739-44.
14. Fritsche LG, Gruber SB, Wu Z, Schmidt EM, Zawistowski M, Moser SE, et al. Association of Polygenic Risk Scores for Multiple Cancers in a Phenome-wide Study: Results from The Michigan Genomics Initiative. The American Journal of Human Genetics. 2018;102(6):1048-61.
15. Zhang Y, Zeng X, Liu P, Hong R, Lu H, Ji H, et al. Association between FGFR2 (rs2981582, rs2420946 and rs2981578) polymorphism and breast cancer susceptibility: a meta-analysis. Oncotarget. 2017;8(2):3454.
16. Zhang L, Long X. Association of three SNPs in TOX3 and breast cancer risk: Evidence from 97275 cases and 128686 controls. Scientific reports. 2015;5:12773.
17. Samson M, Rama R, Swaminathan R, Sridevi V, Nancy KN, Rajkumar T. CYP17 (T34C), CYP19 (Trp39Arg), and FGFR2 (C906T) polymorphisms and the risk of breast cancer in south Indian women. Asian Pac J Cancer Prev. 2009;10(1):111-4.
18. Siddiqui S, Chattopadhyay S, Akhtar MS, Najm MZ, Deo S, Shukla N, et al. A study on genetic variants of Fibroblast growth factor receptor 2 (FGFR2) and the risk of breast cancer from North India. PLoS One. 2014;9(10):e110426.
19. Zhang Y, Lu H, Ji H, Lu L, Liu P, Hong R, et al. Association between rs11200014, rs2981579, and rs1219648 polymorphism and breast cancer susceptibility: A meta-analysis. Medicine. 2017;96(50).