Journal of Gastrointestinal Cancer

, Volume 45, Issue 4, pp 441–447

TGFBR1*6A Polymorphism in Sporadic and Familial Colorectal Carcinoma: a Case-control Study and Systematic Literature Review

  • Tony Ibrahim
  • Charbel Yazbeck
  • Georges Maalouly
  • Maria Baz
  • Fady Haddad
  • Chadi Sabbagh
  • Georges Chahine
Original Research



The role of genetic factors in colorectal cancer pathogenesis is widely accepted. Polymorphisms are actually thought to play a role in the unexplained colorectal cancer (CRC) susceptibility. There is conflicting data regarding the role of the transforming growth factor beta receptor 1 polymorphism 6A (TGFBR1*6A) in the increased incidence of CRC.


Our aim is to test the association between this polymorphism and sporadic/familial CRC in the Lebanese population paying attention to lead time bias in the control group. This is a case-control study conducted in two Lebanese hospital centers.

Materials and Methods

Cases were diagnosed with CRC during the period of 1 year prior to the study. Controls were healthy subjects aged >50 years with a history of normal colonoscopy during the period of 5 years prior to the beginning of the study. A total of 96 cases (57 sporadic/39 familial) and 97 controls were genotyped. The odds ratios for 6A carrier status was statistically significant for sporadic CRC, odds ratio (OR) = 2.314 (95 % confidence interval (CI) 1.030–5.195) but not for familial CRC.


No association was found between 6A carrier status and mean age at diagnosis of CRC. This is the first article in the literature to evaluate the association between 6A polymorphism and total, sporadic, and familial CRC in a single study with reduction of bias in the control group. Results are in conjunction with other studies and meta-analysis.


Transforming growth factor TGFBR1*6A Sporadic colorectal cancer Polymorphism Familial colorectal cancer 


  1. 1.
    Siegel R, Desantis C, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:104–17.PubMedCrossRefGoogle Scholar
  2. 2.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.PubMedCrossRefGoogle Scholar
  3. 3.
    Jones S, Chen WD, Parmigiani D, Diehl F, Beerenwinkel N, Antal T, et al. Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci U S A. 2008;105:4283–8.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Edge B, Byrd R, Compton C, Fritz G, Greene L, Trotti A. AJCC Cancer Staging Manual 7th ed. New York: Springer; 2010.Google Scholar
  5. 5.
    Half E, Bercovich D, Rozen P. Familial adenomatous polyposis. Orphanet J Rare Dis. 2009;4:22.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Macrae F, du Sart D, Nasioulas S. Familial adenomatous polyposis. Best Pract Res Clin Gastroenterol. 2009;23:197–207.PubMedCrossRefGoogle Scholar
  7. 7.
    Xu Y, Pasche B. TGF-β signaling alterations and susceptibility to colorectal cancer. Hum Mol Genet. 2007;16:14–20.CrossRefGoogle Scholar
  8. 8.
    Valle L. Debate about TGFBR1 and the susceptibility to colorectal cancer. World J Gastrointest Oncol. 2012;4:1–8.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Pasche B, Luo Y, Rao PH, Nimer SD, Dmitrovsky E, Caron P, et al. Type I transforming growth factor β receptor maps to 9q22 and exhibits a polymorphism and a rare variant within a polyalanine tract. Cancer Res. 1998;58:2727–32.PubMedGoogle Scholar
  10. 10.
    Carvajal-Carmona LG, Churchman M, Bonilla C, Walther A, Lefèvre JH, Kerr D, et al. Comprehensive assessment of variation at the transforming growth factor β type 1 receptor locus and colorectal cancer predisposition. Proc Natl Acad Sci U S A. 2010;107:7858–62.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Castillejo A, Mata-Balaguer T, Montenegro P, Ochoa E, Lázaro R, Martínez-Cantó A, et al. The TGFBR1*6A allele is not associated with susceptibility to colorectal cancer in a Spanish population: a case-control study. BMC Cancer. 2009;9:193.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Forsti A, Li X, Wagner K, Tavelin B, Enquist K, Palmqvist R, et al. Polymorphisms in the transforming growth factor β 1 pathway in relation to colorectal cancer progression. Genes Chromosomes Cancer. 2010;49:270–81.PubMedGoogle Scholar
  13. 13.
    Pasche B, Kaklamani V, Hou N, Young T, Rademaker A, Peterlongo P, et al. TGFBR1*6A and cancer: a meta-analysis of 12 case-control studies. J Clin Oncol. 2004;22:756–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Pasche B, Kolachana P, Nafa K, Satagopan J, Chen YG, Lo RS, et al. TβR-I(6A) is a candidate tumor susceptibility allele. Cancer Res. 1999;59:5678–82.PubMedGoogle Scholar
  15. 15.
    Samowitz WS, Curtin K, Leppert MF, Slattery ML. Uncommon TGFBRI allele is not associated with increased susceptibility to colon cancer. Genes Chromosomes Cancer. 2001;32:381–3.PubMedCrossRefGoogle Scholar
  16. 16.
    Skoglund Lundin J, Vandrovcova J, Song B, Zhou X, Zelada-Hedman M, Werelius B, et al. TGFBR1 variants TGFBR1(*)6A and Int7G24A are not associated with an increased familial colorectal cancer risk. Br J Cancer. 2009;100:1674–9.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Skoglund J, Song B, Dalén J, Dedorson S, Edler D, Hjern F, et al. Lack of an association between the TGFBR1*6A variant and colorectal cancer risk. Clin Cancer Res. 2007;13:3748–52.PubMedCrossRefGoogle Scholar
  18. 18.
    Stefanovska AM, Efremov GD, Dimovski AJ, Jasar D, Zografski G, Josifovski T, et al. TbetaR-I(6A) polymorphism is not a tumor susceptibility allele in Macedonian colorectal cancer patients. Correspondence re: B. Pasche et al. (1998) Type I TbetaR-I(6A) Is a Candidate Tumor Susceptibility Allele. Cancer Res 58:2727-32. Cancer Res. 2001;61:8351–2.PubMedGoogle Scholar
  19. 19.
    Kaklamani VG, Hou N, Bian Y, Reich J, Offit K, Michel LS, et al. TGFBR1*6A and cancer risk: a meta-analysis of seven case-control studies. J Clin Oncol. 2003;21:3236–43.PubMedCrossRefGoogle Scholar
  20. 20.
    Liao RY, Mao C, Qiu LX, Ding H, Chen Q, Pan HF. TGFBR1*6A/9A polymorphism and cancer risk: a meta-analysis of 13,662 cases and 14,147 controls. Mol Biol Rep. 2010;37:3227–32.PubMedCrossRefGoogle Scholar
  21. 21.
    Zhang X, Wu L, Sheng Y, Zhou W, Huang Z, Qu J, et al. The association of polymorphisms on TGFBR1 and colorectal cancer risk: a meta-analysis. Mol Biol Rep. 2012;39:2567–74.PubMedCrossRefGoogle Scholar
  22. 22.
    Skibber J, Minsky B, Hoff P. Cancer of the colon and rectum. In: De Vita VT, Hellmann Jr S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 6th ed. Philadelphia: Lippincott Williams & Wilkins pp; 2001. p. 1216–71.Google Scholar
  23. 23.
    Calvert PM, Frucht H. The genetics of colorectal cancer. Ann Intern Med. 2002;1:603–12.CrossRefGoogle Scholar
  24. 24.
    Fiocchi C. TGF-β/Smad signaling defects in inflammatory bowel disease: mechanisms and possible novel therapies for chronic inflammation. J Clin Invest. 2001;108:523–6.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Gordon K, Blobe G. Role of transforming growth factor-β superfamily signaling pathways in human disease. Biochim Biophys Acta. 2008;1782:197–228.PubMedCrossRefGoogle Scholar
  26. 26.
    Bian Y, Knobloch TJ, Sadim M, Kaklamani V, Raji A, Yang GY, et al. Somatic acquisition of TGFBR1*6A by epithelial and stromal cells during head and neck and colon cancer development. Hum Mol Genet. 2007;15:3128–35.CrossRefGoogle Scholar
  27. 27.
    Chen T, de Vries EG, Hollema H, Yegen HA, Vellucci VF, Strickler HD, et al. Structural alterations of transforming growth factor-β receptor genes in human cervical carcinoma. Int J Cancer. 1999;2:43–51.CrossRefGoogle Scholar
  28. 28.
    Pasche B, Knobloch TJ, Bian Y, Liu J, Phukan S, Rosman D, et al. Somatic acquisition and signaling of TGFBR1*6A in cancer. JAMA. 2005;294:1634–46.PubMedCrossRefGoogle Scholar
  29. 29.
    Rosman DS, Phukan S, Huang CC, Pasche B. TGFBR1*6A enhances the migration and invasion of MCF-7 breast cancer cells through RhoA activation. Cancer Res. 2008;68:1319–28.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Zhang HT, Zhao J, Zheng SY, Chen XF. Is TGFBR1*6A really associated with increased risk of cancer? J Clin Oncol. 2005;23:7743–4.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Tony Ibrahim
    • 1
  • Charbel Yazbeck
    • 2
  • Georges Maalouly
    • 3
  • Maria Baz
    • 3
  • Fady Haddad
    • 3
  • Chadi Sabbagh
    • 4
  • Georges Chahine
    • 1
  1. 1.Hemato-Oncology DepartmentHotel Dieu de France teaching Hospital of Saint Joseph UniversityBeirutLebanon
  2. 2.Gastro-Enterology DepartmentNotre Dame Du Secours teaching Hospital of Saint Esprit Kaslik UniversityByblosLebanon
  3. 3.Internal Medicine DepartmentHotel Dieu de France teaching Hospital of Saint Joseph UniversityBeirutLebanon
  4. 4.Emergency DepartmentHotel Dieu de France teaching Hospital of Saint Joseph UniversityBeirutLebanon

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