Association of SYK Genetic Variations with Breast Cancer Pathogenesis

  • Shakeel, Shafaq (Department of Biosciences, COMSATS Institute of Information Technology) ;
  • Mahjabeen, Ishrat (Department of Biosciences, COMSATS Institute of Information Technology) ;
  • Kayani, Mahmood Akhtar (Department of Biosciences, COMSATS Institute of Information Technology) ;
  • Faryal, Rani (Department of Biosciences, COMSATS Institute of Information Technology)
  • Published : 2013.05.30


Spleen tyrosine kinase (SYK) is a non-receptor type cytoplasmic protein and a known tumor suppressor gene in breast cancer. Polymorphisms in SYK have been reported to be associated with cell invasion/cell morality and an increased risk of cancer development. In this case control study, all exons of the SYK gene and its exon/ intron boundaries were amplified in 200 breast cancer cases and 100 matched controls and then analyzed by single stranded conformational polymorphism. Amplified products showing altered mobility patterns were sequenced and analyzed. Twelve variations were identified in exonic and intronic regions of DNA encoding SH2 domain and kinase domain of the SYK gene. All of these mutations are novel. Among them, 5 missense mutations were observed in exon 15 while one missense mutation was found in exon 8. In addition to these mutations, six mutations were also identified in intronic regions. We found a significant association between SYK mutations and breast cancer and observed that Glu241Arg, a missense mutation is associated with an increase risk of ~7 fold (OR=6.7, 95% CI=1.54-28.8), Thr581Pro (missense mutation) is associated with increased risk of ~16 fold (OR=15.5, 95%CI=2.07-115.45) and 63367 T>G (missense mutation) is associated with increased risk of ~13 fold (OR=12.8, 95%CI=1.71-96.71) for breast cancer. Significant associations were observed for each of these variations with both late menopause (p<0.01) and early menarche (p<0.005) cases when compared to controls. Our findings suggest that the polymorphic gene SYK may contribute to the development of breast cancer in at least the Pakistani population. This study provides an insight view of SYK which may provide a significant finding for the pharmaceutical and biotechnology industry.


  1. Abbasi S, Azimi C, Othman F (2009). Risk factors for breast cancer in Iranian women: a case control study. Inter J Cancer Res, 5, 1-11.
  2. Ahmad M (2003). Risk factors for breast cancer among women attending breast clinic in University Malaya Medical Centre Kuala Lumpur. NCD Malaysia, 2, 23-31.
  3. Clamp A, Danson S, Clemons M (2003). Hormonal and genetic risk factors for breast cancer. The Surgeon, 1, 23-31.
  4. Coopman CP, Mueller SC (2006). Mini review: the SYK tyrosine kinase: a new negative regulator in tumor growth and progression. Cancer Lett, 241, 159-73.
  5. Coopman PJP, Do MTH, Barth M, et al (2000). The SYK tyrosine kinase suppresses malignant growth of human breast cancer cells. Nature, 406, 742-7.
  6. Harrison AP, Srinivasan K, Binu, VS, et al (2010). Risk factors for breast cancer among women attending a tertiary care hospital in southern India. Inter J Collaborative Res on Internal Medicine & Public Health, 2, 109-16.
  7. Hu YH, Nagata C, Shimizu H, et al (1997). Association of body mass index, physical activity, and reproductive histories with breast cancer: a case-control study in Gifu, Japan. Breast Cancer Res Treat, 43, 65-72.
  8. Hunter S, Sato N, Kim MK, et al (2000). Structural requirements of SYK kinase for Fcgamma receptor-mediated phagocytosis. Exp Hematol, 27, 875-84.
  9. Inayat U, Kayani MA, Rani F (2012). Sporadic mutation and expressional analysis of spleen tyrosine kinase gene in breast cancer. Pol J Pathol, 2, 106-11.
  10. Jemal A, Bray F, Melissa M (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90.
  11. Kanwal S, Kayani MA, Faryal R (2012). Identification of novel SNPs in SYK gene of breast cancer patients: computational analysis of SNPs in the 50UTR. Mol Biol Rep, 39, 8345-51.
  12. Kruk J (2007). Association of lifestyle and other risk factors with breast cancer according to menopausal status: a case-control study in the region of Western Pomerania (Poland). Asian Pac J Cancer Prev, 8, 513-24.
  13. Lakhani SR, Collins N, Sloane JP, et al (1995). Loss of heterozygosity in lobular carcinoma in situ of the breast. J Clin Pathol Mol Pathol, 48, 74-8.
  14. Latour S, Zhang J, Siraganian RP, et al (1998). A unique insert in the linker domain of SYK is necessary for its function in immunoreceptor signalling. EMBO J, 17, 2584-95.
  15. Liu BA, Jablonowski K, Raina M, et al (2006). The human and mouse complement of SH2 domain proteins-establishing the boundaries of phosphotyrosine signaling. Mol Cell, 22, 851-68.
  16. Mahjabeen I, Baig RM, Masood N, et al (2012). Genetic variations in XRCC1 gene in sporadic head and neck cancer (HNC) patients. Pathol Oncol Res, 10, 9567.
  17. Mc Pherson K, Stell CM, Dixon JM (2000). Breast cancerepidemiology, risk factors, and genetics. Br Med J, 321, 624-8.
  18. Minami Y, Ohuchi N, Fukao A (1997). Risk factors for breast cancer: a case-control study of screen-detected breast cancer Miyagi Prefecture, Japan. Breast Cancer Res Treat, 44, 225-33.
  19. Naeem N, Nasir A, Aman Z, et al (2008). Frequency of HER-2/NEU receptor positivity and its association with other features of breast cancer. J Ayub Med Coll Abbottabad, 20, 23-6.
  20. Osborne C, Wilson P, Tripathy D (2004). Oncogenes and tumor suppressor genes in breast cancer: potential diagnostic and therapeutic applications. Oncologist, 9, 361-77.
  21. de Castro RO (2011). Regulation and Function of SYK Tyrosine Kinase in Mast Cell Signaling and Beyond. J Signal Transduction, 10, 507291.
  22. Toyama T, Iwase H, Yamashita H, et al (2002). Reduced expression of the SYK gene is correlated with poor prognosis in human breast cancer. Cancer, 189, 97-102.
  23. Wang L, Duke L, Zhang PS, et al (2003). Alternative splicing disrupts a nuclear localization signal in spleen tyrosine kinase that is required for invasion suppression in breast cancer. Cancer Res, 63, 4724-30.
  24. Yuan Y, Mendez R, Sahin A, et al (2001). Hypermethylation leads to silencing of the SYK gene in human breast cancer. Cancer Res, 61, 5558-61.

Cited by

  1. Germline Variations of Apurinic/Apyrimidinic Endonuclease 1 (APEX1) Detected in Female Breast Cancer Patients vol.15, pp.18, 2014,
  2. Lack of Effects of Dietary Folate Intake on Risk of Breast Cancer: An Updated Meta-analysis of Prospective Studies vol.15, pp.5, 2014,
  3. The role of Syk signaling in antifungal innate immunity of human corneal epithelial cells vol.15, pp.1, 2015,
  4. Effects of Serum Triglycerides on Prostate Cancer and Breast Cancer Risk: A Meta-Analysis of Prospective Studies vol.68, pp.7, 2016,
  5. Alternative splicing of spleen tyrosine kinase differentially regulates colorectal cancer progression vol.12, pp.3, 2016,