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Journal of Gastrointestinal Cancer

, Volume 39, Issue 1–4, pp 118–123 | Cite as

Cyclin D1 A870G Polymorphism in Brazilian Colorectal Cancer Patients

  • Nora Manoukian ForonesEmail author
  • Jacqueline Miranda de Lima
  • Lessileia Gomes de Souza
  • Ismael Dale Cotrim Guerreiro da Silva
Article

Abstract

Introduction

Cyclin D1 (CCND1) is a regulatory protein involved in the cell cycle. A common G to A polymorphism in the CCND1 gene is implicated on the splicing of the CCND1 transcript, and this protein may be associated to a deregulated cell proliferation.

Aim

Correlate the polymorphism A870G of CCND1 to the risk of colorectal cancer (CRC), to environmental risk factors and clinical aspects in Brazilian patients.

Patients and Methods

One hundred twenty-three Brazilian patients with colorectal cancer were matched by age and sex to 120 healthy individuals. PCR-RFLP was performed to investigate the A870G CCND1 genotype.

Results

Between the cases 70 were men, the mean age was 62.6 years, 74.78% were stage II or III, and 91% were well or moderately differentiated. The patients were followed for a mean time of 37.22 months. The frequency of ethanol and fat intake was similar among the groups. Patients with a family history of CRC had a higher frequency of CRC compared with the controls (OR 4.16, CI 1.89–9.16). There was no difference in the frequency of the alleles A (43.8% versus 43.9%) and G (56.3% versus 56.1%) in the groups. In analysis of both control and cancer group, the influence of sex, smoking, alcohol, fiber, or meat intake did not differ significantly according to CCND1 genotype. The genotype AA or AG was associated with an increased risk of CRC (OR 3.63 CI 1.25–10.5) in patients with a family history of cancer. We did not find any association among the genotypes and localization of the tumor or prognosis. Although a difference on age onset of the tumor and genotype was not observed, patients with GG genotype had a mean 8 years lower than the others. This genotype was also associated to an increase risk of metastatic disease (OR 3.47, CI 1.38–8.68, p = 0.024).

Conclusion

We did not find a correlation among the polymorphism of CCND1 A870G and colorectal cancer risk or between this polymorphism and lifestyle habits, diet, or follow-up. GG genotype patients had an increased risk of advanced disease and between the young patients, this genotype was associated to a lower mean age. On the other hand, the genotype AA or AG had been involved to a higher risk of CRC in patients with family history of CRC.

Keywords

cyclin D1 CCND 1 A870G cyclin D1 polymorphism colorectal cancer 

Notes

Acknowledgments

We thank all patients and controls who agreed to join our study. This study was financially supported by Fundaçao de Amparo a Pesquisa do Estado de Sao Paulo, State of Sao Paulo Research, Brazil.

References

  1. 1.
    National Center for Health Statistics. Canters for disease Control and Prevention: US mortality public use data tapes. 1969-2003. http://seer.cancer.gov.
  2. 2.
    Instituto Nacional de Câncer INCA. Estimativas de incidência e mortalidade. http://inca.gov.br.
  3. 3.
    Boyle P, Langman JS. ABC of colorectal cancer. BMJ. 2000;321:805–8. doi: 10.1136/bmj.321.7264.805.PubMedCrossRefGoogle Scholar
  4. 4.
    Houlston RS, Tomilnson IPM. Polymorphism and colorectal cancer tumor risk. Gastroenterology. 2001;121:282–301. doi: 10.1053/gast.2001.26265.PubMedCrossRefGoogle Scholar
  5. 5.
    Arber N, Hibshoosh H, Moss SF, Sutter T, Zhang Y, Begg M, et al. Increased expression of cyclin D1 is an early event in multistage colorectal carcinogenesis. Gastroenterology. 1996;110:669–74. doi: 10.1053/gast.1996.v110.pm8608874.PubMedCrossRefGoogle Scholar
  6. 6.
    Arber N, Doki Y, Han EK, Sgambato A, Zhou P, Kim NH, et al. Antisense to cyclin D1 inhibits the growth and tumorigenicity of human colon cancer cells. Cancer Res. 1997;57:1569–74.PubMedGoogle Scholar
  7. 7.
    Betticher DC, Thatcher N, Altermatt HJ, Hoban P, Ryder WDJ, Heighway J. Oncogene. 1995;11:1005–11.PubMedGoogle Scholar
  8. 8.
    Weinstein IB, Begemann M, Zhou P, Han EK, Sgambato A, Doki Y, et al. Disorders in cell circuitry associated with multistage carcinogenesis: exploitable targets for cancer prevention and therapy. Clin Cancer Res. 1997;3:2696–702.PubMedGoogle Scholar
  9. 9.
    Sawa H, Ohshima TA, Ukita H, Murakami H, Chiba Y, Kamada H, et al. Alternatively spliced forms of cyclin D1 modulate entry into the cell cycle in an inverse manner. Oncogene. 1998;16(13):1701–12. doi: 10.1038/sj.onc.1201691.PubMedCrossRefGoogle Scholar
  10. 10.
    Kong S, Amos CI, Lutra R. Effects of cyclin D1 polymorphism on age of onset of hereditary nonpolyposis colorectal cancer. Cancer Res. 2000;60:249–52.PubMedGoogle Scholar
  11. 11.
    Kong S, Wei Q, Amos CI, Lynch PM, Levin B, Zong J, et al. Cyclin D1 polymorphism and increased risk of colorectal cancer at young age. J Natl Cancer Inst. 2001;93(14):1106–8. doi: 10.1093/jnci/93.14.1106.PubMedCrossRefGoogle Scholar
  12. 12.
    Porter TR, Richards FM, Houlston RS, Evans DG, Jankowski JA, Macdonald F, et al. Contribution of cyclin D1 (CCND1) and E-cadherin (CDH1) polymorphisms to familial and sporadic colorectal cancer. Oncogene. 2002;21:1928–33. doi: 10.1038/sj.onc.1205245.PubMedCrossRefGoogle Scholar
  13. 13.
    McKay JA, Douglas JJ, Ross VG, Curran S, Murray GI, Cassidy J, et al. Cyclin D1 protein expression and gene polymorphism in colorectal cancer. Int J Cancer. 2000;88:77–81. doi: 10.1002/1097-0215(20001001)88:1<77::AID-IJC12>3.0.CO;2-O.PubMedCrossRefGoogle Scholar
  14. 14.
    Butterworth AS, Higgins JP, Pharoah P. Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. Eur J Cancer. 2006;42:216–7. doi: 10.1016/j.ejca.2005.09.023.PubMedCrossRefGoogle Scholar
  15. 15.
    National Comprehensive Cancer Network. Colorectal cancer guidelines. http://nccn.org/professionals/physician_gls/PDF/colon.pdf.
  16. 16.
    Bala S, Peltomaki P. Cyclin D1 as a genetic modifier in hereditary nonpolyposis colorectal cancer. Cancer Res. 2001;61:6042–45.PubMedGoogle Scholar
  17. 17.
    Le Marchand L, Seifried A, Lum-Jones A, Donlon T. Wilkens LR Association of the cyclin D1 A870G polymorphism with advanced colorectal cancer. JAMA. 2003;290:2843–8. doi: 10.1001/jama.290.21.2843.PubMedCrossRefGoogle Scholar
  18. 18.
    Jiang J, Wang J, Suzuki S, Gajalakshmi V, Kuriki K, Zhao Y, et al. Elevated risk of colorectal cancer associated with the AA genotype of the cyclin D1 A870G polymorphism in an Indian population. J Cancer Res Clin Oncol. 2006;132:193–9. doi: 10.1007/s00432-005-0039-7.PubMedCrossRefGoogle Scholar
  19. 19.
    Lewis RC, Bostick RM, Xie D, Deng Z, Wargovich MJ, Fina MF, et al. Polymorphism of cyclin D1 gene CCND1 and risk for incidental sporadic colorectal adenomas. Can Res. 2003;63:8549–53.Google Scholar
  20. 20.
    Huang WS, Tang R, Lin PY, Changchien CR, Chen JS, Chiang JM, et al. Impact of the cyclin D1 A870G polymorphism on susceptibility to sporadic colorectal cancer in Taiwan. Dis colon rectum. 2006;19:602–8. doi: 10.1007/s10350-005-0311-6.CrossRefGoogle Scholar
  21. 21.
    Schernhammer ES, Tranah GJ, Giovannucci E, Chan AT, Ma J, Colditz GA, et al. Cyclin D1 A870G polymorphism and the risk of colorectal cancer and adenoma. Br J Cancer. 2006;94:928–34. doi: 10.1038/sj.bjc.6603007.PubMedCrossRefGoogle Scholar
  22. 22.
    Hong Y, Eu KW, Seow-Choen F, Fook-Chong S, Cheah PY. GG genotype of cylin D1 G870A polymorphism. Eur J Cancer. 2005;41:1037–44. doi: 10.1016/j.ejca.2005.01.009.PubMedCrossRefGoogle Scholar
  23. 23.
    Probst-Hensh NM, Sun CL, Van Den Berg D, Ceschi M, Koh WP, Yu MC. The effect of the cyclin D1 (CCND1) A870G polymorphism on colorectal cancer risk is modified by glutathione-S-transferase polymorphisms and isothiocyanate intake in the Singapore Chinese Health Study. Carcinogenesis. 2006;27:2475–82. doi: 10.1093/carcin/bgl116.CrossRefGoogle Scholar
  24. 24.
    Tan XL, Nieters A, Kropp S, Hoffmeister M, Brenner H, Chang-Claude J. The association of cyclin D1 G870A and E-cadherin C-160A polymorphisms with the risk of colorectal cancer in a case control study and meta-analysis. Int J cancer. 2008;122:2573–80. doi: 10.1002/ijc.23363.PubMedCrossRefGoogle Scholar
  25. 25.
    Grünhage F, Jungck M, Lamberti C, Berg C, Becker U, Schulte-Witte H, et al. Association of familial colorectal cancer with variants in the e-cadherin (CDH1) and cyclin D1 (CCND1) genes. Int J Colorectal Dis. 2008;32:147–54. doi: 10.1007/s00384-007-0388-6.CrossRefGoogle Scholar
  26. 26.
    Mathias C, Branigan K, Jahnke V, et al. Polymorphism within the cyclin D1 gene is associated with prognosis in patients with squamous cell carcinoma of head and neck. Clin Cancer Research. 1998;4:2411–18.Google Scholar
  27. 27.
    Zatyka M, Silva NF, Cliford SC. Identification of cyclin D1 and other novel targets for the von Hippel Lindau tumour supresso gene by expression array analysis and investigation of cyclin D1 genotype as a modifier in von Hippel Lindau disease. Cancer Res. 2002;62:3803–11.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Nora Manoukian Forones
    • 1
    • 2
    Email author
  • Jacqueline Miranda de Lima
    • 1
  • Lessileia Gomes de Souza
    • 1
  • Ismael Dale Cotrim Guerreiro da Silva
    • 1
  1. 1.Oncology Group/Gastroenterology DivisionUniversidade Federal de São Paulo (UNIFESP/EPM)São PauloBrazil
  2. 2.Disciplina de Gastroenterologia ClínicaUniversidade Federal de Sao PauloSão PauloBrazil

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