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Molecular Biology Reports

, Volume 39, Issue 5, pp 5977–5984 | Cite as

Variant allele of CHEK2 is associated with a decreased risk of esophageal cancer lymph node metastasis in a Chinese population

  • Haiyong Gu
  • Wanshan Qiu
  • Ying Wan
  • Guowen Ding
  • Weifeng Tang
  • Chao Liu
  • Yijun Shi
  • Yijang Chen
  • Suocheng Chen
Article

Abstract

Growing evidence suggests that the checkpoint kinase 2 (CHEK2) signaling pathway occupies a central position in the signaling networks of DNA-damage signaling. Many functional and molecular epidemiological studies have evaluated the association between genetic variants of CHEK2 and various cancers. To evaluate the relationship between CHEK2 functional genetic variants and esophageal cancer risk and the risk of lymph node metastasis among a Chinese population. We genotyped CHEK2 rs738722, rs2236141 and rs2236142 single nucleotide polymorphisms (SNPs) using the matrix assisted laser desorption/ionization time-of-flight mass spectrometry assay in a case–controlled study, including 380 esophageal cancer cases and 380 healthy controls in a Chinese population. We found that none of the three polymorphisms achieved significant difference in their distributions between esophageal cancer cases and controls. Multiple logistic regression analyses revealed that esophageal cancer risk was not associated significantly with the variant genotypes of the three CHEK2 polymorphisms as compared with their wild-type genotypes. However, we found that functional variant rs738722 and rs2236142 in CHEK2 might contribute to susceptibility to lymph node metastasis. Our data did not support a significant association between CHEK2 SNPs and the risk of esophageal cancer. Functional variant CHEK2 rs738722 and rs2236142 might contribute to lymph node metastasis susceptibility. The CT allele of SNP rs738722 and the GC allele of SNP rs2236142 might be a protective factor of the risk for lymph node metastasis of esophageal cancer.

Keywords

CHEK2 Polymorphisms Esophageal cancer Lymph node metastasis Molecular epidemiology 

Abbreviations

CI

Confidence interval

CHEK2

Checkpoint kinase 2

LD

Linkage disequilibrium

OR

Odds ratio

SNPs

Single nucleotide polymorphisms

Notes

Acknowledgments

This work was supported in part by National Natural Science Foundation of China (81101889), the Jiangsu Province Natural Science Foundation (BK2009207) and Social Development Foundation of Zhenjiang (SH2010017).

References

  1. 1.
    Kapeller P, Barber R, Vermeulen RJ, Ader H, Scheltens P, Freidl W, Almkvist O, Moretti M, del Ser T, Vaghfeldt P, Enzinger C, Barkhof F, Inzitari D, Erkinjunti T, Schmidt R, Fazekas F (2003) Visual rating of age-related white matter changes on magnetic resonance imaging: scale comparison, interrater agreement, and correlations with quantitative measurements. Stroke 34:441–445PubMedCrossRefGoogle Scholar
  2. 2.
    Liu JF, Wang QZ, Hou J (2004) Surgical treatment for cancer of the oesophagus and gastric cardia in Hebei, China. Br J Surg 91:90–98PubMedCrossRefGoogle Scholar
  3. 3.
    Muir CS, McKinney PA (1992) Cancer of the oesophagus: a global overview. Eur J Cancer Prev 1:259–264PubMedCrossRefGoogle Scholar
  4. 4.
    Layke JC, Lopez PP (2006) Esophageal cancer: a review and update. Am Fam Physician 73:2187–2194PubMedGoogle Scholar
  5. 5.
    Xing D, Tan W, Lin D (2003) Genetic polymorphisms and susceptibility to esophageal cancer among Chinese population (review). Oncol Rep 10:1615–1623PubMedGoogle Scholar
  6. 6.
    Lee SB, Kim SH, Bell DW, Wahrer DC, Schiripo TA, Jorczak MM, Sgroi DC, Garber JE, Li FP, Nichols KE, Varley JM, Godwin AK, Shannon KM, Harlow E, Haber DA (2001) Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. Cancer Res 61:8062–8067PubMedGoogle Scholar
  7. 7.
    Stevens C, Smith L, La Thangue NB (2003) Chk2 activates E2F-1 in response to DNA damage. Nat Cell Biol 5:401–409PubMedCrossRefGoogle Scholar
  8. 8.
    Yang S, Kuo C, Bisi JE, Kim MK (2002) PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2. Nat Cell Biol 4:865–870PubMedCrossRefGoogle Scholar
  9. 9.
    Bartek J, Falck J, Lukas J (2001) CHK2 kinase—a busy messenger. Natl Rev Mol Cell Biol 2:877–886CrossRefGoogle Scholar
  10. 10.
    Takai H, Naka K, Okada Y, Watanabe M, Harada N, Saito S, Anderson CW, Appella E, Nakanishi M, Suzuki H, Nagashima K, Sawa H, Ikeda K, Motoyama N (2002) Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. EMBO J 21:5195–5205PubMedCrossRefGoogle Scholar
  11. 11.
    Bartek J, Lukas J (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3:421–429PubMedCrossRefGoogle Scholar
  12. 12.
    Matsuoka S, Rotman G, Ogawa A, Shiloh Y, Tamai K, Elledge SJ (2000) Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc Natl Acad Sci USA 97:10389–10394PubMedCrossRefGoogle Scholar
  13. 13.
    Chaturvedi P, Eng WK, Zhu Y, Mattern MR, Mishra R, Hurle MR, Zhang X, Annan RS, Lu Q, Faucette LF, Scott GF, Li X, Carr SA, Johnson RK, Winkler JD, Zhou BB (1999) Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Oncogene 18:4047–4054PubMedCrossRefGoogle Scholar
  14. 14.
    Ahn JY, Schwarz JK, Piwnica-Worms H, Canman CE (2000) Threonine 68 phosphorylation by ataxia telangiectasia mutated is required for efficient activation of Chk2 in response to ionizing radiation. Cancer Res 60:5934–5936PubMedGoogle Scholar
  15. 15.
    Falck J, Mailand N, Syljuasen RG, Bartek J, Lukas J (2001) The ATM–Chk2–Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410:842–847PubMedCrossRefGoogle Scholar
  16. 16.
    Chehab NH, Malikzay A, Appel M, Halazonetis TD (2000) Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Genes Dev 14:278–288PubMedGoogle Scholar
  17. 17.
    Shieh SY, Ahn J, Tamai K, Taya Y, Prives C (2000) The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev 14:289–300PubMedGoogle Scholar
  18. 18.
    Lee JS, Collins KM, Brown AL, Lee CH, Chung JH (2000) hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 404:201–204PubMedCrossRefGoogle Scholar
  19. 19.
    Zhang S, Lu J, Zhao X, Wu W, Wang H, Lu J, Wu Q, Chen X, Fan W, Chen H, Wang F, Hu Z, Jin L, Wei Q, Shen H, Huang W, Lu D (2010) A variant in the CHEK2 promoter at a methylation site relieves transcriptional repression and confers reduced risk of lung cancer. Carcinogenesis 31:1251–1258PubMedCrossRefGoogle Scholar
  20. 20.
    Hung RJ, Baragatti M, Thomas D, McKay J, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates D, Foretova L, Janout V, Bencko V, Chabrier A, Moullan N, Canzian F, Hall J, Boffetta P, Brennan P (2007) Inherited predisposition of lung cancer: a hierarchical modeling approach to DNA repair and cell cycle control pathways. Cancer Epidemiol Biomarkers Prev 16:2736–2744PubMedCrossRefGoogle Scholar
  21. 21.
    Cybulski C, Gorski B, Huzarski T, Masojc B, Mierzejewski M, Debniak T, Teodorczyk U, Byrski T, Gronwald J, Matyjasik J, Zlowocka E, Lenner M, Grabowska E, Nej K, Castaneda J, Medrek K, Szymanska A, Szymanska J, Kurzawski G, Suchy J, Oszurek O, Witek A, Narod SA, Lubinski J (2004) CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 75:1131–1135PubMedCrossRefGoogle Scholar
  22. 22.
    Dong X, Wang L, Taniguchi K, Wang X, Cunningham JM, McDonnell SK, Qian C, Marks AF, Slager SL, Peterson BJ, Smith DI, Cheville JC, Blute ML, Jacobsen SJ, Schaid DJ, Tindall DJ, Thibodeau SN, Liu W (2003) Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet 72:270–280PubMedCrossRefGoogle Scholar
  23. 23.
    Kleibl Z, Havranek O, Hlavata I, Novotny J, Sevcik J, Pohlreich P, Soucek P (2009) The CHEK2 gene I157T mutation and other alterations in its proximity increase the risk of sporadic colorectal cancer in the Czech population. Eur J Cancer 45:618–624PubMedCrossRefGoogle Scholar
  24. 24.
    Abnet CC, Freedman ND, Hu N, Wang Z, Yu K, Shu XO, Yuan JM, Zheng W, Dawsey SM, Dong LM, Lee MP, Ding T, Qiao YL, Gao YT, Koh WP, Xiang YB, Tang ZZ, Fan JH, Wang C, Wheeler W, Gail MH, Yeager M, Yuenger J, Hutchinson A, Jacobs KB, Giffen CA, Burdett L, Fraumeni JF Jr, Tucker MA, Chow WH, Goldstein AM, Chanock SJ, Taylor PR (2010) A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma. Nat Genet 42:764–767PubMedCrossRefGoogle Scholar
  25. 25.
    Schaeffeler E, Zanger UM, Eichelbaum M, Asante-Poku S, Shin JG, Schwab M (2008) Highly multiplexed genotyping of thiopurine s-methyltransferase variants using MALD-TOF mass spectrometry: reliable genotyping in different ethnic groups. Clin Chem 54:1637–1647PubMedCrossRefGoogle Scholar
  26. 26.
    Falck J, Lukas C, Protopopova M, Lukas J, Selivanova G, Bartek J (2001) Functional impact of concomitant versus alternative defects in the Chk2–p53 tumour suppressor pathway. Oncogene 20:5503–5510PubMedCrossRefGoogle Scholar
  27. 27.
    Miller CW, Ikezoe T, Krug U, Hofmann WK, Tavor S, Vegesna V, Tsukasaki K, Takeuchi S, Koeffler HP (2002) Mutations of the CHK2 gene are found in some osteosarcomas, but are rare in breast, lung, and ovarian tumors. Genes Chromosom Cancer 33:17–21PubMedCrossRefGoogle Scholar
  28. 28.
    Koppert LB, Schutte M, Abbou M, Tilanus HW, Dinjens WN (2004) The CHEK2(*)1100delC mutation has no major contribution in oesophageal carcinogenesis. Br J Cancer 90:888–891PubMedCrossRefGoogle Scholar
  29. 29.
    Easton D, McGuffog L, Thompson D, Dunning A, Tee L, Baynes C, Healey C, Pharoah P, Ponder B, Seal S, Barfoot R, Sodha N, Eeles R, Stratton M, Rahman N, Peto J, Spurdle AB, Chen XQ, Chenevix-Trench G, Hopper JL, Giles GG, McCredie MRE, Syrjakoski K, Holli K, Kallioniemi O, Eerola H, Vahteristo P, Blomqvist C, Nevanlinna H, Kataja V, Mannermaa A, Dork T, Bremer M, Devilee P, de Bock GH, Krol-Warmerdam EMM, Kroese-Jansema K, Wijers-Koster P, Cornelisse CJ, Tollenaar R, Meijers-Heijboer H, Berns E, Nagel J, Foekens J, Klijn JGM, Schutte M (2004) CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet 74:1175–1182Google Scholar
  30. 30.
    Zhang S, Phelan CM, Zhang P, Rousseau F, Ghadirian P, Robidoux A, Foulkes W, Hamel N, McCready D, Trudeau M, Lynch H, Horsman D, De Matsuda ML, Aziz Z, Gomes M, Costa MM, Liede A, Poll A, Sun P, Narod SA (2008) Frequency of the CHEK2 1100delC mutation among women with breast cancer: an international study. Cancer Res 68:2154–2157PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Haiyong Gu
    • 1
  • Wanshan Qiu
    • 2
  • Ying Wan
    • 3
  • Guowen Ding
    • 1
  • Weifeng Tang
    • 1
  • Chao Liu
    • 1
  • Yijun Shi
    • 1
  • Yijang Chen
    • 4
  • Suocheng Chen
    • 1
  1. 1.Department of Cardiothoracic SurgeryAffiliated People’s Hospital of Jiangsu UniversityZhenjiangChina
  2. 2.Children’s Hospital of Fudan UniversityShanghaiChina
  3. 3.Department of Clinical LaboratoryThe Affiliated Hospital of Jiangsu UniversityZhenjiangChina
  4. 4.Department of Thoracic & Cardiac SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina

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