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Role of Caspase 8, Caspase 9 and Bcl-2 polymorphisms in papillary thyroid carcinoma risk in Han Chinese population

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Abstract

Dysregulation of apoptosis plays a key role in carcinogenesis. This study was designed to investigate the association of apoptosis-related gene Caspase 8, Caspase 9 and Bcl-2 polymorphisms with papillary thyroid carcinoma (PTC) susceptibility. We undertook a case–control study of 118 patients and 213 controls to investigate the association between Caspase 8 (-652 6 N ins/del), Caspase 9 (-1263 A>G) and Bcl-2 (-938 C>A) polymorphisms and PTC susceptibility by polymerase chain reaction restriction–fragment length polymorphism and DNA sequencing methods. We further analyzed the distribution of genotype frequency, as well as the association of genotype with clinicopathological characteristics. Overall, no statistically significant association was observed in Caspase 8 (-652 6 N ins/del). Nevertheless, Caspase 9 -1263 GG genotype was at increased risk of PTC (P = 0.045; odds ratio (OR) = 1.12). Furthermore, GG genotype thyroid cancers were significantly more common in older patients than AA or AG genotypes PTC and in cases of advanced pathological stages. However, Bcl-2 -938 AA genotype demonstrated a protective effect in PTCs (P = 0.004; OR = 0.35). Polymorphism in Caspase 9 (-1263 A>G) was observed to be associated with susceptibility of PTC. However, Bcl-2 (-938 C>A) polymorphism indicated to play a protective role in susceptibility to PTC. Nevertheless, further investigation with a larger sample size is needed to support our results.

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References

  1. Urken ML. Prognosis and management of invasive well-differentiated thyroid cancer. Otolaryngol Clin North Am. 2010;43(2):301–28. doi:10.1016/j.otc.2010.02.002. viii.

    Article  PubMed  Google Scholar 

  2. Johnson NA, Tublin ME. Postoperative surveillance of differentiated thyroid carcinoma: rationale, techniques, and controversies. Radiology. 2008;249(2):429–44. doi:10.1148/radiol.2492071313.

    Article  PubMed  Google Scholar 

  3. Kuma K, Matsuzuka F, Kobayashi A, Hirai K, Morita S, Miyauchi A, et al. Outcome of long standing solitary thyroid nodules. World J Surg. 1992;16(4):583–7. discussion 7–8.

    Article  PubMed  CAS  Google Scholar 

  4. Kuma K, Matsuzuka F, Yokozawa T, Miyauchi A, Sugawara M. Fate of untreated benign thyroid nodules: results of long-term follow-up. World J Surg. 1994;18(4):495–8. discussion 9.

    Article  PubMed  CAS  Google Scholar 

  5. Nikiforov YE. Is ionizing radiation responsible for the increasing incidence of thyroid cancer? Cancer. 2010;116(7):1626–8. doi:10.1002/cncr.24889.

    Article  PubMed  Google Scholar 

  6. Hegedus L. Clinical practice. The thyroid nodule. N Engl J Med. 2004;351(17):1764–71. doi:10.1056/NEJMcp031436.

    Article  PubMed  Google Scholar 

  7. Paschke R, Schmid KW, Gartner R, Mann K, Dralle H, Reiners C. Epidemiology, pathophysiology, guideline-adjusted diagnostics, and treatment of thyroid nodules. Med Klin (Munich). 2010;105(2):80–7. doi:10.1007/s00063-010-1011-9.

    Article  Google Scholar 

  8. Dean DS, Gharib H. Epidemiology of thyroid nodules. Best Pract Res Clin Endocrinol Metab. 2008;22(6):901–11. doi:10.1016/j.beem.2008.09.019.

    Article  PubMed  Google Scholar 

  9. Marx J. Oncology. Recruiting the cell’s own guardian for cancer therapy. Science. 2007;315(5816):1211–3. doi:10.1126/science.315.5816.1211.

    Article  PubMed  CAS  Google Scholar 

  10. Nakagawa A, Shi Y, Kage-Nakadai E, Mitani S, Xue D. Caspase-dependent conversion of Dicer ribonuclease into a death-promoting deoxyribonuclease. Science. 2010;328(5976):327–34. doi:10.1126/science.1182374.

    Article  PubMed  CAS  Google Scholar 

  11. Shivapurkar N, Reddy J, Chaudhary PM, Gazdar AF. Apoptosis and lung cancer: a review. J Cell Biochem. 2003;88(5):885–98. doi:10.1002/jcb.10440.

    Article  PubMed  CAS  Google Scholar 

  12. Hajra KM, Liu JR. Apoptosome dysfunction in human cancer. Apoptosis. 2004;9(6):691–704. doi:10.1023/B:APPT.0000045786.98031.1d.

    Article  PubMed  CAS  Google Scholar 

  13. Wang W, Spitz MR, Yang H, Lu C, Stewart DJ, Wu X. Genetic variants in cell cycle control pathway confer susceptibility to lung cancer. Clin Cancer Res. 2007;13(19):5974–81. doi:10.1158/1078-0432.CCR-07-0113.

    Article  PubMed  CAS  Google Scholar 

  14. Ye Y, Yang H, Grossman HB, Dinney C, Wu X, Gu J. Genetic variants in cell cycle control pathway confer susceptibility to bladder cancer. Cancer. 2008;112(11):2467–74. doi:10.1002/cncr.23472.

    Article  PubMed  CAS  Google Scholar 

  15. Umar M, Upadhyay R, Kumar S, Ghoshal UC, Mittal B. CASP8-652 6 N del and CASP8 IVS12-19 G >A gene polymorphisms and susceptibility/prognosis of ESCC: a case control study in northern Indian population. J Surg Oncol. 2011;103(7):716–23. doi:10.1002/jso.21881.

    Article  PubMed  CAS  Google Scholar 

  16. Sun T, Gao Y, Tan W, Ma S, Shi Y, Yao J, et al. A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers. Nat Genet. 2007;39(5):605–13. doi:10.1038/ng2030.

    Article  PubMed  CAS  Google Scholar 

  17. Haiman CA, Garcia RR, Kolonel LN, Henderson BE, Wu AH, Le Marchand L. A promoter polymorphism in the CASP8 gene is not associated with cancer risk. Nat Genet. 2008;40(3):259–60. doi:10.1038/ng0308-259. author reply 60–1.

    Article  PubMed  CAS  Google Scholar 

  18. Gangwar R, Mandhani A, Mittal RD. Caspase 9 and caspase 8 gene polymorphisms and susceptibility to bladder cancer in north Indian population. Ann Surg Oncol. 2009;16(7):2028–34. doi:10.1245/s10434-009-0488-3.

    Article  PubMed  Google Scholar 

  19. Czabotar PE, Lessene G. Bcl-2 family proteins as therapeutic targets. Curr Pharm Des. 2010;16(28):3132–48.

    Article  PubMed  CAS  Google Scholar 

  20. Park BL, Kim LH, Cheong HS, Cho HY, Kim EM, Shin HD, et al. Identification of variants in cyclin D1 (CCND1) and B-Cell CLL/lymphoma 2 (BCL2). J Hum Genet. 2004;49(8):449–54. doi:10.1007/s10038-004-0173-0.

    Article  PubMed  CAS  Google Scholar 

  21. Bachmann HS, Otterbach F, Callies R, Nuckel H, Bau M, Schmid KW, et al. The AA genotype of the regulatory BCL2 promoter polymorphism (938 C>A) is associated with a favorable outcome in lymph node negative invasive breast cancer patients. Clin Cancer Res. 2007;13(19):5790–7. doi:10.1158/1078-0432.CCR-06-2673.

    Article  PubMed  CAS  Google Scholar 

  22. Edge SB. American Joint Committee on Cancer. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.

    Google Scholar 

  23. Theodoropoulos GE, Michalopoulos NV, Panoussopoulos SG, Taka S, Gazouli M. Effects of caspase-9 and survivin gene polymorphisms in pancreatic cancer risk and tumor characteristics. Pancreas. 2010;39(7):976–80. doi:10.1097/MPA.0b013e3181d705d4.

    Article  PubMed  CAS  Google Scholar 

  24. Zhang N, Li X, Tao K, Jiang L, Ma T, Yan S, et al. BCL-2 (-938 C>A) polymorphism is associated with breast cancer susceptibility. BMC Med Genet. 2011;12:48. doi:10.1186/1471-2350-12-48.

    Article  PubMed  CAS  Google Scholar 

  25. Thatte U, Dahanukar S. Apoptosis: clinical relevance and pharmacological manipulation. Drugs. 1997;54(4):511–32.

    Article  PubMed  CAS  Google Scholar 

  26. Fennell DA. Caspase regulation in non-small cell lung cancer and its potential for therapeutic exploitation. Clin Cancer Res. 2005;11(6):2097–105. doi:10.1158/1078-0432.CCR-04-1482.

    Article  PubMed  CAS  Google Scholar 

  27. Hengartner MO. The biochemistry of apoptosis. Nature. 2000;407(6805):770–6. doi:10.1038/35037710.

    Article  PubMed  CAS  Google Scholar 

  28. Kaufmann SH, Gores GJ. Apoptosis in cancer: cause and cure. Bioessays. 2000;22(11):1007–17. doi:10.1002/1521-1878(200011)22:11<1007:AID-BIES7>3.0.CO;2-4.

    Article  PubMed  CAS  Google Scholar 

  29. Nicholson DW, Thornberry NA. Caspases: killer proteases. Trends Biochem Sci. 1997;22(8):299–306.

    Article  PubMed  CAS  Google Scholar 

  30. Mathew R, White E. FLIPping the balance between apoptosis and proliferation in thyroid cancer. Clin Cancer Res. 2006;12(12):3648–51. doi:10.1158/1078-0432.CCR-06-0620.

    Article  PubMed  CAS  Google Scholar 

  31. Majid A, Tsoulakis O, Walewska R, Gesk S, Siebert R, Kennedy DB, et al. BCL2 expression in chronic lymphocytic leukemia: lack of association with the BCL2 938 A>C promoter single nucleotide polymorphism. Blood. 2008;111(2):874–7. doi:10.1182/blood-2007-07-098681.

    Article  PubMed  CAS  Google Scholar 

  32. Kaderi MA, Norberg M, Murray F, Merup M, Sundstrom C, Roos G, et al. The BCL-2 promoter (-938 C>A) polymorphism does not predict clinical outcome in chronic lymphocytic leukemia. Leukemia. 2008;22(2):339–43. doi:10.1038/sj.leu.2405042.

    Article  PubMed  CAS  Google Scholar 

  33. Zenz T, Benner A, Duhrsen U, Durig J, Dohner H, Siffert W, et al. BCL2-938 C>A polymorphism and disease progression in chronic lymphocytic leukemia. Leuk Lymphoma. 2009;50(11):1837–42. doi:10.3109/10428190903207530.

    Article  PubMed  CAS  Google Scholar 

  34. Twiddy D, Cain K. Caspase-9 cleavage, do you need it? Biochem J. 2007;405(1):e1–2. doi:10.1042/BJ20070617.

    PubMed  CAS  Google Scholar 

  35. Park JY, Park JM, Jang JS, Choi JE, Kim KM, Cha SI, et al. Caspase 9 promoter polymorphisms and risk of primary lung cancer. Hum Mol Genet. 2006;15(12):1963–71. doi:10.1093/hmg/ddl119.

    Article  PubMed  CAS  Google Scholar 

  36. Pittman AM, Broderick P, Sullivan K, Fielding S, Webb E, Penegar S, et al. CASP8 variants D302H and -652 6 N ins/del do not influence the risk of colorectal cancer in the United Kingdom population. Br J Cancer. 2008;98(8):1434–6. doi:10.1038/sj.bjc.6604314.

    Article  PubMed  CAS  Google Scholar 

  37. Frank B, Rigas SH, Bermejo JL, Wiestler M, Wagner K, Hemminki K, et al. The CASP8-652 6 N del promoter polymorphism and breast cancer risk: a multicenter study. Breast Cancer Res Treat. 2008;111(1):139–44. doi:10.1007/s10549-007-9752-z.

    Article  PubMed  CAS  Google Scholar 

  38. Young RL, Korsmeyer SJ. A negative regulatory element in the bcl-2 5′-untranslated region inhibits expression from an upstream promoter. Mol Cell Biol. 1993;13(6):3686–97.

    PubMed  CAS  Google Scholar 

  39. Nuckel H, Frey UH, Bau M, Sellmann L, Stanelle J, Durig J, et al. Association of a novel regulatory polymorphism (-938 C>A) in the BCL2 gene promoter with disease progression and survival in chronic lymphocytic leukemia. Blood. 2007;109(1):290–7. doi:10.1182/blood-2006-03-007567.

    Article  PubMed  Google Scholar 

  40. Hirata H, Hinoda Y, Nakajima K, Kikuno N, Suehiro Y, Tabatabai ZL, et al. The bcl2-938CC genotype has poor prognosis and lower survival in renal cancer. J Urol. 2009;182(2):721–7. doi:10.1016/j.juro.2009.03.081.

    Article  PubMed  CAS  Google Scholar 

  41. Lehnerdt GF, Franz P, Bankfalvi A, Grehl S, Kelava A, Nuckel H, et al. The regulatory BCL2 promoter polymorphism (-938 C>A) is associated with relapse and survival of patients with oropharyngeal squamous cell carcinoma. Ann Oncol. 2009;20(6):1094–9. doi:10.1093/annonc/mdn763.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Endocrinology, School of Clinical Medicine, Binzhou Medical University, No. 661, Yellow-River Second Street, Binzhou, 256603, China

    Ying-Xue Wang, Xiu-Yun Wang, Chang-Mei Liu & Su-Guo Yu

  2. Department of Radiotherapy, Cancer Center, Sun Yat-Sen University, Guangzhou, China

    Lei Zhao

  3. State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou, China

    Lei Zhao

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  1. Ying-Xue Wang
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Correspondence to Ying-Xue Wang.

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Ying-Xue Wang and Lei Zhao are contributed equally to this work.

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Wang, YX., Zhao, L., Wang, XY. et al. Role of Caspase 8, Caspase 9 and Bcl-2 polymorphisms in papillary thyroid carcinoma risk in Han Chinese population. Med Oncol 29, 2445–2451 (2012). https://doi.org/10.1007/s12032-011-0121-8

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