Breast Cancer Research and Treatment

, Volume 112, Issue 1, pp 81–87 | Cite as

TGFβ1 (Leu10Pro), p53 (Arg72Pro) can predict for increased risk for breast cancer in south Indian women and TGFβ1 Pro (Leu10Pro) allele predicts response to neo-adjuvant chemo-radiotherapy

  • Thangarajan Rajkumar
  • Mani Samson
  • Ranganathan Rama
  • Veluswami Sridevi
  • Urmila Mahji
  • Rajaraman Swaminathan
  • Nirmala K. Nancy


The breast cancer incidence has been increasing in the south Indian women. A case (n = 250)–control (n = 500) study was undertaken to investigate the role of Single Nucleotide Polymorphisms (SNP’s) in GSTM1 (Present/Null); GSTP1 (Ile105Val), p53 (Arg72Pro), TGFβ1 (Leu10Pro), c-erbB2 (Ile655Val), and GSTT1 (Null/Present) in breast cancer. In addition, the value of the SNP’s in predicting primary tumor’s pathologic response following neo-adjuvant chemo-radiotherapy was assessed. Genotyping was done using PCR (GSTM1, GSTT1), Taqman Allelic discrimination assay (GSTP1, c-erbB2) and PCR-CTPP (p53 and TGFβ1). None of the gene SNP’s studied were associated with a statistically significant increased risk for the breast cancer. However, combined analysis of the SNP’s showed that p53 (Arg/Arg and Arg/Pro) with TGFβ1 (Pro/Pro and Leu/Pro) were associated with greater than 2 fold increased risk for breast cancer in Univariate (P = 0.01) and Multivariate (P = 0.003) analysis. There was no statistically significant association for the GST family members with the breast cancer risk. TGFβ1 (Pro/Pro) allele was found to predict complete pathologic response in the primary tumour following neo-adjuvant chemo-radiotherapy (OR = 6.53 and 10.53 in Univariate and Multivariate analysis respectively) (P = 0.004) and was independent of stage. This study suggests that SNP’s can help predict breast cancer risk in south Indian women and that TGFβ1 (Pro/Pro) allele is associated with a better pCR in the primary tumour.


Breast cancer SNP GSTM1 (Present/Null) GSTP1 (Ile105Val) p53 (Arg72Pro) TGFβ1 (Leu10Pro) c-erbB2 (Ile655Val) GSTT1 (Null/Present) Response to neo-adjuvant therapy 



We would like to thank the Chennai Willingdon Corporate Foundation for providing financial support for this project. We also thank the patients and subjects who participated as controls, in the study.


  1. 1.
    Shanta V, Swaminathan R, Kavitha M (2005) Cancer incidence and mortality in Chennai, India, Year 2002. Madras Metropolitan Tumor Registry, National Cancer Registry Program, Cancer Institute (WIA), ChennaiGoogle Scholar
  2. 2.
    Samson M, Swaminathan R, Rama R, Sridevi V, Nancy KN, Rajkumar T (2007) Role of GSTM1 (Null/Present), GSTP1 (Ile105Val) and P53 (Arg72Pro) Genetic polymorphisms and the risk of breast cancer - A case control study from south India. Asian Pac J Cancer Prev 8:253–257PubMedGoogle Scholar
  3. 3.
    Wagner TM, Moslinger RA, Muhr D, Langbauer G, Hirtenlehner K et al (1998) BRCA1-related breast cancer in Austrian breast and ovarian cancer families: specific BRCA1 mutations and pathological characteristics. Int J Cancer 77:354–360PubMedCrossRefGoogle Scholar
  4. 4.
    Couch FJ, Wang XY, Wu GJ, Qian J, Jenkins RB, James CD (1999) Localization of PS6K to chromosomal region 17q23 and determination of its amplification in breast cancer. Cancer Res 59:1408–1411PubMedGoogle Scholar
  5. 5.
    Dunning AM, Healey CS, Pharoah PD, Teare MD, Ponder BA, Easton DF (1999) A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev 8:843–854PubMedGoogle Scholar
  6. 6.
    Wang H, Zeng ZC, Bui TA, DiBiase SJ, Qin W, Xia F, Powell SN, Iliakis G et al (2001) Non-homologous end-joining of ionizing radiation-induced DNA double-stranded breaks in human tumor cells deficient in BRCA1 or BRCA21. Cancer Res 61:270–277PubMedGoogle Scholar
  7. 7.
    Ameyaw MM, Tayeb M, Thornton N, Folayan G, Tariq M, Mobarek A et al (2002) Ethnic variation in the HER-2 codon 655 genetic polymorphism previously associated with breast cancer. J Hum Genet 47:172–175PubMedCrossRefGoogle Scholar
  8. 8.
    Dunning AM, Ellis PD, McBride S, Kirschenlohr HL, Healey CS et al (2003) A transforming growth factorbeta1 signal peptide variant increases secretion in vitro and is associated with increased incidence of invasive breast cancer. Cancer Res 63(10):2610–2615PubMedGoogle Scholar
  9. 9.
    Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447:1087–1094PubMedCrossRefGoogle Scholar
  10. 10.
    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 39:870–874PubMedCrossRefGoogle Scholar
  11. 11.
    Pharoah PD, Tyrer J, Dunning AM, Easton DF, Ponder BA (2007) Association between common variation in 120 candidate genes and breast cancer risk. PLoS Genet 3(3):e42PubMedCrossRefGoogle Scholar
  12. 12.
    Lee KM, Park SK, Hamajima N, Tajima K, Yoo KY, Shin A et al (2005) Genetic polymorphisms of TGFβ11 & TNF-β and breast cancer risk. Breast Cancer Res Treat 90:149–155PubMedCrossRefGoogle Scholar
  13. 13.
    Krajinovic M, Labuda D, Richer C, Karimi S, Sinnett D (1999) A susceptibility to childhood acute lymphoblastic leukemia: influence of CYP1A1, CYP2D6, GSTM1, and GSTT1 genetic polymorphisms. Blood 93:1496–1501PubMedGoogle Scholar
  14. 14.
    Beslow NE, Day NE (1980) Statistical methods in cancer research. Vol I. The analysis of cases-control studies. IARC Scientific Publications No 32, IARC, LyonGoogle Scholar
  15. 15.
    Kaplan EL, Meier P (1958) Non parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
  16. 16.
    Cox A, Dunning AM, Garcia-Closas M, Balasubramanian S, Reed MW, Pooley KA, Scollen S et al (2007) A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 39(5):688CrossRefGoogle Scholar
  17. 17.
    Xie D, Shu XO, Deng Z, Wen WQ, Creek KE, Dai Q et al (2000) Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk. J Natl Cancer Inst 92:412–417PubMedCrossRefGoogle Scholar
  18. 18.
    Pinto D, Vasconcelos A, Costa S, Pereira D, Rodrigues H et al (2004) HER2 polymorphism and breast cancer risk in Portugal. Eur J Cancer Prev 13:177–181PubMedCrossRefGoogle Scholar
  19. 19.
    Tommasi S, Fedele V, Lacalamita R, Bruno M, Schittulli F, Ginzinger D et al (2007) 655Val and 1170Pro ERBB2 SNPs in familial breast cancer risk and BRCA1 alterations. Cell Oncol 29:241–248PubMedGoogle Scholar
  20. 20.
    Benusiglio PR, Lesueur F, Luccarini C, Conroy DM, Shah M et al (2005) Common ERBB2 polymorphisms and risk of breast cancer in a white British population: a case-control study. Breast Cancer Res 7:204–209CrossRefGoogle Scholar
  21. 21.
    Han W, Kang D, Lee JE, Park IA, Choi JY, Lee KM et al (2005) A haplotype analysis of HER-2 gene polymorphisms: association with breast cancer risk, HER-2 protein expression in the tumor, and disease recurrence in Korea. Clin Cancer Res 11:4775–4778PubMedCrossRefGoogle Scholar
  22. 22.
    Nelson SE, Gould MN, Hampton JM, Trentham-Dietz A (2005) A case-control study of the HER2 Ile655Val polymorphism in relation to risk of invasive breast cancer. Breast Cancer Res 7:357–364CrossRefGoogle Scholar
  23. 23.
    Cox DG, Hankinson SE, Hunter DJ (2005) The erbB2/HER2/neu receptor polymorphism Ile655Val and breast cancer risk. Pharmacogenet Genomics 15:447–450PubMedCrossRefGoogle Scholar
  24. 24.
    Vogl FD, Taioli E, Maugard C, Zheng W, Pinto LF et al (2004) Glutathione S-transferases M1, T1, and P1 and breast cancer: a pooled analysis. Cancer Epidemiol Biomarkers Prev 9:1473–1479Google Scholar
  25. 25.
    Edvardsen H, Kristensen VN, Grenaker Alnaes GI, Bøhn M, Erikstein B et al (2007) Germline glutathione S-transferase variants in breast cancer: relation to diagnosis and cutaneous long-term adverse effects after two fractionation patterns of radiotherapy. Int J Radiat Oncol Biol Phys 67:163–171Google Scholar
  26. 26.
    Park SK, Yim DS, Yoon KS, Choi IM, Choi JY, Yoo KY et al (2004) Combined effect of GSTM1, GSTT1, and COMT genotypes in individual breast cancer risk. Breast Cancer Res Treat 88:55–62PubMedCrossRefGoogle Scholar
  27. 27.
    Steck SE, Gaudet MM, Britton JA, Teitelbaum SL, Terry MB et al (2007) Interactions among GSTM1, GSTT1 and GSTP1 polymorphisms, cruciferous vegetable intake and breast cancer risk. Carcinogenesis 128:1954–1959CrossRefGoogle Scholar
  28. 28.
    Spurdle AB, Chang JH, Byrnes GB, Chen X, Dite GS et al (2007) A systematic approach to analyzing gene-gene interactions: polymorphisms at the microsomal epoxide hydrolase EPHX and glutathione S-transferase GSTM1, GSTT1, and GSTP1 loci and breast cancer risk. Cancer Epidemiol Biomarkers Prev 16:769–774PubMedCrossRefGoogle Scholar
  29. 29.
    Andreassen CN, Alsner J, Overgaard J, Herskind C, Haviland J et al (2005) TGFB1 polymorphisms are associated with risk of late normal tissue complications in the breast after radiotherapy for early breast cancer. Radiother Oncol 75:18–21PubMedCrossRefGoogle Scholar
  30. 30.
    DeMichele A, Aplenc R, Botbyl J, Colligan T, Wray L et al (2005) Drug-metabolizing enzyme polymorphisms predict clinical outcome in a node-positive breast cancer cohort. J Clin Oncol 23:5552–5559PubMedCrossRefGoogle Scholar
  31. 31.
    Yang G, Shu XO, Ruan ZX, Cai QY, Jin F et al (2005) Genetic polymorphisms in glutathione-S-transferase genes (GSTM1, GSTT1, GSTP1) and survival after chemotherapy for invasive breast carcinoma. Cancer 103:52–58PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2007

Authors and Affiliations

  • Thangarajan Rajkumar
    • 1
  • Mani Samson
    • 1
  • Ranganathan Rama
    • 2
  • Veluswami Sridevi
    • 3
  • Urmila Mahji
    • 4
  • Rajaraman Swaminathan
    • 2
  • Nirmala K. Nancy
    • 1
  1. 1.Department of Molecular OncologyCancer Institute (WIA)ChennaiIndia
  2. 2.Department of Epidemiology and Tumour RegistryCancer Institute (WIA)ChennaiIndia
  3. 3.Department of Surgical OncologyCancer Institute (WIA)ChennaiIndia
  4. 4.Department of PathologyCancer Institute (WIA)ChennaiIndia

Personalised recommendations