Breast Cancer Research and Treatment

, Volume 126, Issue 3, pp 739–747 | Cite as

Role of ethnic variations in TNF-α and TNF-β polymorphisms and risk of breast cancer in India

  • Singh Pooja
  • Amirtharaj Francis
  • Hemant Kumar Bid
  • Sandeep Kumar
  • Singh Rajender
  • K. Ramalingam
  • Kumarasamy Thangaraj
  • Rituraj Konwar


TNF-α and -β, the multi-functional pro-inflammatory cytokines, are known to play important roles in both tumor progression and destruction based on their concentrations. Growth factors and various stimuli such as cytokines regulate proliferation of the breast epithelial cells. Therefore, the polymorphisms in the genes encoding these signaling molecules could affect the risk of breast cancer. We have investigated selected genetic polymorphisms in TNF-α promoter (rs1800629, −308 G>A and rs361525, −238 G>A) and TNF-β intron 1 (rs909253, +252 A>G) in ethnically two different case–control groups from India. The study included 200 cases and 200 controls from an Indo-European (North Indian) group, and 265 cases and 237 controls from a Dravidian (South Indian) group. Genotyping of a total of 902 individuals was done by direct DNA sequencing. None of the polymorphisms showed significant association with breast cancer in the Indo-European group; however, all the three polymorphisms showed strong association with breast cancer in the Dravidian group. Further, sub-group analysis in the Indo-European group showed no significant difference between pre-menopausal cases and controls or between post-menopausal cases and controls at any of the loci analyzed. However, all the polymorphisms in the Dravidian group were significantly associated with pre-menopausal but not with post-menopausal breast cancer. In conclusion, TNF-α and -β polymorphisms are strongly associated with breast cancer in the Dravidian but not in the Indo-European group.


Breast cancer TNF-α TNF-β Polymorphism Cytokines 



The authors are thankful to the patients for their participation in the study. We thank the Indian Council of Medical Research (ICMR), Govt. of India, for providing financial support (Grant Number 5/13/12/207-NCDIII). This manuscript bears CDRI communication no 7962.

Conflict of interest

All authors declare that they have no conflict of interest.


  1. 1.
    Kellen E, Vansant G, Christiaens MR, Neven P, Van Limbergen E (2009) Lifestyle changes and breast cancer prognosis: a review. Breast Cancer Res Treat 114:13–22PubMedCrossRefGoogle Scholar
  2. 2.
    Tsongalis GJ, Ricci A Jr (2003) Breast cancer as a model of realistic challenges in pharmacogenomics. Clin Biochem 36:89–94PubMedCrossRefGoogle Scholar
  3. 3.
    Chopra R (2001) The Indian scene. J Clin Oncol 19:106S–111SPubMedGoogle Scholar
  4. 4.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics, 2008. CA Cancer J Clin 58:71–96PubMedCrossRefGoogle Scholar
  5. 5.
    Azmy IA, Balasubramanian SP, Wilson AG, Stephenson TJ, Cox A, Brown NJ, Reed MW (2004) Role of tumour necrosis factor gene polymorphisms (−308 and −238) in breast cancer susceptibility and severity. Breast Cancer Res 6:R395–R400PubMedCrossRefGoogle Scholar
  6. 6.
    Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K (2000) Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343:78–85PubMedCrossRefGoogle Scholar
  7. 7.
    Bazzoni F, Beutler B (1996) The tumor necrosis factor ligand and receptor families. N Engl J Med 334:1717–1725PubMedCrossRefGoogle Scholar
  8. 8.
    Leek RD, Landers R, Fox SB, Ng F, Harris AL, Lewis CE (1998) Association of tumour necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma. Br J Cancer 77:2246–2251PubMedCrossRefGoogle Scholar
  9. 9.
    Palladino MA Jr, Shalaby MR, Kramer SM, Ferraiolo BL, Baughman RA, Deleo AB, Crase D, Marafino B, Aggarwal BB, Figari IS et al (1987) Characterization of the antitumor activities of human tumor necrosis factor-alpha and the comparison with other cytokines: induction of tumor-specific immunity. J Immunol 138:4023–4032PubMedGoogle Scholar
  10. 10.
    Robinson SC, Coussens LM (2005) Soluble mediators of inflammation during tumor development. Adv Cancer Res 93:159–187PubMedCrossRefGoogle Scholar
  11. 11.
    Carroll MC, Katzman P, Alicot EM, Koller BH, Geraghty DE, Orr HT, Strominger JL, Spies T (1987) Linkage map of the human major histocompatibility complex including the tumor necrosis factor genes. Proc Natl Acad Sci U S A 84:8535–8539PubMedCrossRefGoogle Scholar
  12. 12.
    Balkwill F (2006) TNF-alpha in promotion and progression of cancer. Cancer Metastasis Rev 25:409–416PubMedCrossRefGoogle Scholar
  13. 13.
    Wu S, Boyer CM, Whitaker RS, Berchuck A, Wiener JR, Weinberg JB, Bast RC Jr (1993) Tumor necrosis factor alpha as an autocrine and paracrine growth factor for ovarian cancer: monokine induction of tumor cell proliferation and tumor necrosis factor alpha expression. Cancer Res 53:1939–1944PubMedGoogle Scholar
  14. 14.
    Balkwill F (2002) Tumor necrosis factor or tumor promoting factor? Cytokine Growth Factor Rev 13:135–141PubMedCrossRefGoogle Scholar
  15. 15.
    Smith CA, Farrah T, Goodwin RG (1994) The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell 76:959–962PubMedCrossRefGoogle Scholar
  16. 16.
    Kroeger KM, Steer JH, Joyce DA, Abraham LJ (2000) Effects of stimulus and cell type on the expression of the −308 tumour necrosis factor promoter polymorphism. Cytokine 12:110–119PubMedCrossRefGoogle Scholar
  17. 17.
    Bouma G, Xia B, Crusius JB, Bioque G, Koutroubakis I, Von Blomberg BM, Meuwissen SG, Peña AS (1996) Distribution of four polymorphisms in the tumour necrosis factor (TNF) genes in patients with inflammatory bowel disease (IBD). Clin Exp Immunol 103:391–396PubMedCrossRefGoogle Scholar
  18. 18.
    Louis E, Franchimont D, Piron A, Gevaert Y, Schaaf-Lafontaine N, Roland S, Mahieu P, Malaise M, De Groote D, Louis R, Belaiche J (1998) Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol 113:401–406PubMedCrossRefGoogle Scholar
  19. 19.
    Park KS, Mok JW, Ko HE, Tokunaga K, Lee MH (2002) Polymorphisms of tumour necrosis factors A and B in breast cancer. Eur J Immunogenet 29:7–10PubMedCrossRefGoogle Scholar
  20. 20.
    Lee KM, Park SK, Hamajima N, Tajima K, Yoo KY, Shin A, Noh DY, Ahn SH, Hirvonen A, Kang D (2005) Genetic polymorphisms of TGF-beta1 & TNF-beta and breast cancer risk. Breast Cancer Res Treat 90:149–155PubMedCrossRefGoogle Scholar
  21. 21.
    Kohaar I, Tiwari P, Kumar R, Nasare V, Thakur N, Das BC, Bharadwaj M (2009) Association of single nucleotide polymorphisms (SNPs) in TNF-LTA locus with breast cancer risk in Indian population. Breast Cancer Res Treat 114:347–355PubMedCrossRefGoogle Scholar
  22. 22.
    Sobin LH, Wittekind CH (1997) TNM: classification of malignant tumours. In: International union against cancer, 5th edn. Wiley-Liss, New York, USGoogle Scholar
  23. 23.
    Bloom H, Richardson W (1957) Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer 11:359–377PubMedCrossRefGoogle Scholar
  24. 24.
    Thangaraj K, Joshi MB, Reddy AG, Gupta NJ, Chakravarty B, Singh L (2002) CAG repeat expansion in the androgen receptor gene is not associated with male infertility in Indian populations. J Androl 23:815–818PubMedGoogle Scholar
  25. 25.
    Thangaraj K, Singh L, Reddy AG, Rao VR, Sehgal SC, Underhill PA, Pierson M, Frame IG, Hagelberg E (2003) Genetic affinities of the Andaman Islanders, a vanishing human population. Curr Biol 13:86–93PubMedCrossRefGoogle Scholar
  26. 26.
    Giordani L, Bruzzi P, Lasalandra C, Quaranta M, Schittulli F, Della Ragione F, Iolascon A (2003) Association of breast cancer and polymorphisms of interleukin-10 and tumor necrosis factor-alpha genes. Clin Chem 49:1664–1667PubMedCrossRefGoogle Scholar
  27. 27.
    Smith KC, Bateman AC, Fussell HM, Howell WM (2004) Cytokine gene polymorphisms and breast cancer susceptibility and prognosis. Eur J Immunogenet 31:167–173PubMedCrossRefGoogle Scholar
  28. 28.
    Kamali-Sarvestani E, Merat A, Talei AR (2005) Polymorphism in the genes of alpha and beta tumor necrosis factors (TNF-alpha and TNF-beta) and gamma interferon (IFN-gamma) among Iranian women with breast cancer. Cancer Lett 223:113–119PubMedCrossRefGoogle Scholar
  29. 29.
    Scola L, Vaglica M, Crivello A, Palmeri L, Forte GI, Macaluso MC, Giacalone A, Di Noto L, Bongiovanni A, Raimondi C, Accardo A, Verna R, Candore G, Caruso C, Lio D, Palmeri S (2006) Cytokine gene polymorphisms and breast cancer susceptibility. Ann N Y Acad Sci 1089:104–109PubMedCrossRefGoogle Scholar
  30. 30.
    Gaudet MM, Egan KM, Lissowska J, Newcomb PA, Brinton LA, Titus-Ernstoff L, Yeager M, Chanock S, Welch R, Peplonska B, Trentham-Dietz A, Garcia-Closas M (2007) Genetic variation in tumor necrosis factor and lymphotoxin-alpha (TNF-LTA) and breast cancer risk. Hum Genet 121:483–490PubMedCrossRefGoogle Scholar
  31. 31.
    Sirotkovic-Skerlev M, Cacev T, Krizanac S, Kulić A, Pavelic K, Kapitanovic S (2007) TNF alpha promoter polymorphisms analysis in benign and malignant breast lesions. Exp Mol Pathol 83:54–58PubMedCrossRefGoogle Scholar
  32. 32.
    Gonullu G, Basturk B, Evrensel T, Oral B, Gozkaman A, Manavoglu O (2007) Association of breast cancer and cytokine gene polymorphism in Turkish women. Saudi Med J 28:1728–1733PubMedGoogle Scholar
  33. 33.
    Ostashkin AS, Malivanova TF, Iurchenko VA, Mazurenko NN (2008) Tumor necrosis factor gene polymorphisms in breast cancer patients. Genetika 44:1275–1280PubMedGoogle Scholar
  34. 34.
    Fang F, Yao L, Yu XJ, Yu L, Wu Q, Yu L (2010) TNF alpha −308 G/A polymorphism is associated with breast cancer risk: a meta-analysis involving 10,184 cases and 12,911 controls. Breast Cancer Res Treat 122:267–271PubMedCrossRefGoogle Scholar
  35. 35.
    Gaudet MM, Milne RL, Cox A, Camp NJ, Goode EL, Humphreys MK, Dunning AM, Morrison J, Giles GG, Severi G, Baglietto L, English DR, Couch FJ, Olson JE, Wang X, Chang-Claude J, Flesch-Janys D, Abbas S, Salazar R, Mannermaa A, Kataja V, Kosma VM, Lindblom A, Margolin S, Heikkinen T et al (2009) Five polymorphisms and breast cancer risk: results from the Breast Cancer Association Consortium. Cancer Epidemiol Biomarkers Prev 18:1610–1616PubMedCrossRefGoogle Scholar
  36. 36.
    Chouchane L, Ahmed SB, Baccouche S, Remadi S (1997) Polymorphism in the tumor necrosis factor-alpha promotor region and in the heat shock protein 70 genes associated with malignant tumors. Cancer 80:1489–1496PubMedCrossRefGoogle Scholar
  37. 37.
    Dhandapany PS, Sadayappan S, Xue Y, Powell GT, Rani DS, Nallari P, Rai TS, Khullar M, Soares P, Bahl A, Tharkan JM, Vaideeswar P, Rathinavel A, Narasimhan C, Ayapati DR, Ayub Q, Mehdi SQ, Oppenheimer S, Richards M, Price A, Patterson N, Reich D, Singh L, Tyler-Smith C, Thangaraj K (2009) A common Cardiac Myosin Binding Protein C variant associated with cardiomyopathies in South Asia. Nat Genet 41:187–191PubMedCrossRefGoogle Scholar
  38. 38.
    Reich D, Thangaraj K, Patterson N, Price AL, Singh L (2009) Reconstructing Indian Population History. Nature 461:489–494PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Singh Pooja
    • 1
  • Amirtharaj Francis
    • 2
  • Hemant Kumar Bid
    • 1
  • Sandeep Kumar
    • 3
  • Singh Rajender
    • 1
  • K. Ramalingam
    • 2
  • Kumarasamy Thangaraj
    • 4
  • Rituraj Konwar
    • 1
  1. 1.Endocrinology DivisionCentral Drug Research Institute (CSIR)LucknowIndia
  2. 2.Department of Advanced Zoology & BiotechnologyGovernment Arts CollegeChennaiIndia
  3. 3.Department of SurgeryChhatrapati Sahuji Maharaj Medical University (CSMMU)LucknowIndia
  4. 4.Centre for Cellular and Molecular Biology (CSIR)HyderabadIndia

Personalised recommendations