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Association of Cytotoxic T Lymphocyte-associated antigen-4 gene haplotype with the susceptibility to gastric cancer

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Abstract

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) was widely accepted as a pivotal molecule in downregulating T-cell mediated immune responses. In this study we investigated the polymorphisms which would impact the CTLA-4 gene expression and function to assess the association with the risk of gastric cancer. 205 gastric cancer patients and 262 healthy controls were included in the case-control study. PCR and restriction fragment length polymorphism (RFLP) methods were performed to identify the +49A/G and promoter −1661A/G polymorphisms. The promoter −1772T/C polymorphism was detected by PCR amplification refractory mutation system (ARMS) technique. A significant difference was observed between case and control groups. The frequency of +49A/G polymorphism AG and −1661A/G polymorphism GG genotype were significantly higher in patients than in controls (OR = 2.15, OR = 1.88, respectively). No significant difference was found in the allelic frequency of −1772T/C polymorphism between cases and controls (P = 0.478). By the haplotype analysis, logistic regression showed the frequency of haplotype A (GAT) and D (AGT) in the case group revealed significant difference compared with in control group(OR = 2.00, P < 0.001; OR = 1.62, P = 0.043, respectively). Our findings implied the genetic variations within CTLA-4 gene would be a critical risk factor to the susceptibility of gastric cancer.

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Abbreviations

CTLA-4:

Cytotoxic T lymphocyte-associated antigen-4

ARMS:

Amplification refractory mutation system

RFLP:

Restriction fragment length polymorphism

References

  1. Leung WK, Wu MS, Kakugawa Y, Kim JJ, Yeoh KG, Goh KL, Wu KC, Wu DC, Sollano J, Kachintorn U, Gotoda T, Lin JT, You WC, Ng EK, Sung JJ (2008) Screening for gastric cancer in Asia: current evidence and practice. Lancet Oncol 9:279–287. doi:10.1016/S1470-2045(08)70072-X

    Article  PubMed  Google Scholar 

  2. Catalano V, Labianca R, Beretta GD, Gatta G, de Braud F, Van Cutsem E (2005) Gastric cancer. Crit Rev Oncol Hematol 54:209–241. doi:10.1016/j.critrevonc.2005.01.002

    Article  PubMed  Google Scholar 

  3. Tsugane S, Sasazuki S (2007) Diet and the risk of gastric cancer: review of epidemiological evidence. Gastric Cancer 10:75–83. doi:10.1007/s10120-007-0420-0

    Article  PubMed  Google Scholar 

  4. Mayne ST, Navarro SA (2002) Diet, obesity and reflux in the etiology of adenocarcinomas of the esophagus and gastric cardia in humans. J Nutr 132:3467S–3470S. doi:10.1541-6100/jn.2002-132.3647

    CAS  PubMed  Google Scholar 

  5. Hatakeyama M (2009) Helicobacter pylori and gastric carcinogenesis. J Gastroenterol 44:239–248. doi:10.1007/s00535-009-0014-1

    Article  CAS  PubMed  Google Scholar 

  6. Fijneman RJ (2005) Genetic predisposition to sporadic cancer: how to handle major effects of minor genes? Cell Oncol 27:281–292. doi:10.8606/j.1570-58702005.27-281

    CAS  PubMed  Google Scholar 

  7. Hadinia A, Hossieni SV, Erfani N, Saberi-Firozi M, Fattahi MJ, Ghaderi A (2007) CTLA-4 gene promoter and exon 1 polymorphisms in Iranian patients with gastric and colorectal cancers. J Gastroenterol Hepatol 22:2283–2287. doi:10.1111/j.1440-1746.2007.04862.x

    Article  CAS  PubMed  Google Scholar 

  8. Sohn MH, Kim SH, Song TW, Kim KW, Kim ES, Park HS, Kim KE (2007) Cytotoxic T lymphocyte-associated antigen-4 gene polymorphisms confer susceptibility to atopic asthma in Korean children. Pediatr Pulmonol 42:542–547. doi:10.1002/ppul.20622

    Article  PubMed  Google Scholar 

  9. Wong YK, Chang KW, Cheng CY, Liu CJ (2006) Association of CTLA-4 gene polymorphism with oral squamous cell carcinoma. J Oral Pathol Med 35:51–54. doi:10.1111/j.1600-0714.2005.00377.x

    Article  CAS  PubMed  Google Scholar 

  10. Ligers A, Teleshova N, Masterman T, Huang WX, Hillert J (2001) CTLA-4 gene expression is influenced by promoter and exon 1 polymorphisms. Genes Immun 2:145–152. doi:10.1038/sj.gene.6363752

    Article  CAS  PubMed  Google Scholar 

  11. Bouqbis L, Izaabel H, Akhayat O, Perez-Lezaun A, Calafell F, Bertranpetit J, Comas D (2003) Association of the CTLA4 promoter region (−1661G allele) with type 1 diabetes in the South Moroccan population. Genes Immun 4:132–137. doi:10.1038/sj.gene.6363933

    Article  CAS  PubMed  Google Scholar 

  12. Hudson LL, Rocca K, Song YW, Pandey JP (2002) CTLA-4 gene polymorphisms in systemic lupus erythematosus: a highly significant association with a determinant in the promoter region. Hum Genet 111:452–455. doi:10.1007/s00439-002-0807-2

    Article  CAS  PubMed  Google Scholar 

  13. Sameni S, Ghayumi MA, Mortazavi G, Faghih Z, Kashef MA, Ghaderi A (2009) Lack of association between interleukin-13 gene polymorphisms (−1055 C/T and +2044 G/A) in Iranian patients with lung cancer. Mol Biol Rep 36:1001–1005. doi:10.1007/s11033-008-9273-9

    Article  CAS  PubMed  Google Scholar 

  14. Agarwal K, Czaja AJ, Jones DE, Donaldson PT (2000) Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis. Hepatology 31:49–53. doi:10.1002/hep.510310110

    Article  CAS  PubMed  Google Scholar 

  15. Fernandez-Blanco L, Perez-Pampin E, Gomez-Reino JJ, Gonzalez A (2004) A CTLA-4 polymorphism associated with susceptibility to systemic lupus erythematosus. Arthritis Rheum 50:328–329. doi:10.1002/art.11444

    Article  CAS  PubMed  Google Scholar 

  16. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989. doi:10.1086/319501

    Article  CAS  PubMed  Google Scholar 

  17. Mohamadynejad P, Saadat M (2007) Genetic polymorphisms of XRCC1 (at codons 194 and 399) in Shiraz population (Fars province, southern Iran). Mol Biol Rep 35:669–672. doi:10.1007/s11033-007-9138-7

    Article  PubMed  Google Scholar 

  18. Erfani N, Razmkhah M, Talei AR, Pezeshki AM, Doroudchi M, Monabati A, Ghaderi A (2006) Cytotoxic T lymphocyte antigen-4 promoter variants in breast cancer. Cancer Genet Cytogenet 165:114–120. doi:10.1016/j.cancergencyto.2005.07.020

    Article  CAS  PubMed  Google Scholar 

  19. Movva S, Verschraegen C (2009) The monoclonal antibody to cytotoxic T lymphocyte antigen 4, ipilimumab (MDX-010), a novel treatment strategy in cancer management. Expert Opin Biol Ther 9:231–241. doi:10.1517/14712590802643347

    Article  CAS  PubMed  Google Scholar 

  20. Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP, Toes RE, Offringa R, Melief CJ (2001) Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 194:823–832. doi:10.1540-9538/2001.194-823

    Article  CAS  PubMed  Google Scholar 

  21. Schneider H, Downey J, Smith A, Zinselmeyer BH, Rush C, Brewer JM, Wei B, Hogg N, Garside P, Rudd CE (2006) Reversal of the TCR stop signal by CTLA-4. Science 313:1972–1975. doi:10.1126/science.1131078

    Article  CAS  PubMed  Google Scholar 

  22. Kouki T, Sawai Y, Gardine CA, Fisfalen ME, Alegre ML, DeGroot LJ (2000) CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves’ disease. J Immunol 165:6606–6611. doi:10.1550-6606/j.2000.165-6606

    CAS  PubMed  Google Scholar 

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Correspondence to Ziping Chen.

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Ruiping Hou and Bangwei Cao contributed equally to this work.

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Hou, R., Cao, B., Chen, Z. et al. Association of Cytotoxic T Lymphocyte-associated antigen-4 gene haplotype with the susceptibility to gastric cancer. Mol Biol Rep 37, 515–520 (2010). https://doi.org/10.1007/s11033-009-9705-1

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  • DOI: https://doi.org/10.1007/s11033-009-9705-1

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