Skip to main content

Advertisement

SpringerLink
Log in

Functional polymorphisms of matrix metalloproteinase-9 and survival in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

To investigate the prognostic role of major matrix metalloproteinase (MMP) gene polymorphisms in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated with chemoradiotherapy. Four hundred twenty-one consecutive NPC patients were prospectively recruited. Two hundred patients were randomly selected as the training cohort, and the remaining 221 patients were the validation cohort. Twelve polymorphisms in the MMP-1, 2, 3, 7, 8, and 9 genes were genotyped by ligase detection reaction-PCR. MMP-9 rs2250889 PR/RR (HR = 2.287, 95 % CI 1.400–3.735) and rs17576 RQ/QQ (HR = 2.347, 95 % CI 1.431–3.849) genotypes were significantly related with increased death risk in the training cohort. Analysis of the validation cohort confirmed these results (rs2250889: HR = 2.231, 95 % CI 1.281–3.886; rs17576: HR = 2.987, 95 % CI 1.674–5.330). Multivariate analysis showed that rs17576 (HR = 2.284, 95 % CI 1.123–4.643, P = 0.023) was still an independent prognostic factor. The MMP-9 rs17576 is a novel independent prognostic marker in patients with locoregionally advanced NPC treated with chemoradiotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Cao SM, Simons MJ, Qian CN. The prevalence and prevention of nasopharyngeal carcinoma in China. Chin J Cancer. 2011;30(2):114–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Wee JT, Ha TC, Loong SL, Qian CN. Is nasopharyngeal cancer really a “Cantonese cancer”? Chin J Cancer. 2010;29(5):517–26.

    Article  CAS  PubMed  Google Scholar 

  3. Chen QY, Wen YF, Guo L, Liu H, Huang PY, Mo HY, et al. Concurrent chemoradiotherapy vs radiotherapy alone in stage II nasopharyngeal carcinoma: phase III randomized trial. J Natl Cancer Inst. 2011;103(23):1761–70.

    Article  PubMed  Google Scholar 

  4. Su SF, Han F, Zhao C, Chen CY, Xiao WW, Li JX, et al. Long-term outcomes of early-stage nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy alone. Int J Radiat Oncol Biol Phys. 2012;82(1):327–33.

    Article  PubMed  Google Scholar 

  5. Lai SZ, Li WF, Chen L, Luo W, Chen YY, Liu LZ, et al. How does intensity-modulated radiotherapy versus conventional two-dimensional radiotherapy influence the treatment results in nasopharyngeal carcinoma patients? Int J Radiat Oncol Biol Phys. 2011;80(3):661–8.

    Article  PubMed  Google Scholar 

  6. Lee AW, Tung SY, Chua DT, Ngan RK, Chappell R, Tung R, et al. Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst. 2010;102(15):1188–98.

    Article  PubMed  Google Scholar 

  7. Wang HY, Sun BY, Zhu ZH, Chang ET, To KF, Hwang JS, et al. Eight-signature classifier for prediction of nasopharyngeal [corrected] carcinoma survival. J Clin Oncol. 2011;29(34):4516–25.

    Article  PubMed  Google Scholar 

  8. Chambers AF, Matrisian LM. Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst. 1997;89(17):1260–70.

    Article  CAS  PubMed  Google Scholar 

  9. Roy R, Yang J, Moses MA. Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. J Clin Oncol. 2009;27(31):5287–97.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Decock J, Ji-Rong L, Laxton RC, Shu XO, Hodgkinson C, Hendrickx W, et al. Association of matrix metalloproteinase-8 gene variation with breast cancer prognosis. Cancer Res. 2007;67(21):10214–21.

    Article  CAS  PubMed  Google Scholar 

  11. Beeghly-Fadiel A, Long JR, Gao YT, Li C, Qu SM, Cai QY, et al. Common MMP-7 polymorphisms and breast cancer susceptibility: a multistage study of association and functionality. Cancer Res. 2008;68(15):6453–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Beeghly-Fadiel A, Shu XO, Long JR, Li C, Cai QY, Cai H, et al. Genetic polymorphisms in the MMP-7 gene and breast cancer survival. Int J Cancer. 2009;124(1):208–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Hettiaratchi A, Hawkins NJ, McKenzie G, Ward RL, Hunt JE, Wakefield D, et al. The collagenase-1 (MMP-1) gene promoter polymorphism - 1607/2G is associated with favourable prognosis in patients with colorectal cancer. Brit J Cancer. 2007;96(5):783–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Langers AMJ, Sier CFM, Hawinkels LJAC, Kubben FJGM, van Duijn W, van der Reijden JJ, et al. MMP-2 geno-phenotype is prognostic for colorectal cancer survival, whereas MMP-9 is not. Brit J Cancer. 2008;98(11):1820–3.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Hu Z, Huo X, Lu D, Qian J, Zhou J, Chen Y, et al. Functional polymorphisms of matrix metalloproteinase-9 are associated with risk of occurrence and metastasis of lung cancer. Clin Cancer Res. 2005;11(15):5433–9.

    Article  CAS  PubMed  Google Scholar 

  16. Jin G, Miao R, Hu Z, Xu L, Huang X, Chen Y, et al. Putative functional polymorphisms of MMP9 predict survival of NSCLC in a Chinese population. Int J Cancer. 2009;124(9):2172–8.

    Article  CAS  PubMed  Google Scholar 

  17. Nasr HB, Mestiri S, Chahed K, Bouaouina N, Gabbouj S, Jalbout M, et al. Matrix metalloproteinase-1 (−1607) 1G/2G and -9 (−1562) C/T promoter polymorphisms: susceptibility and prognostic implications in nasopharyngeal carcinomas. Clin Chim Acta. 2007;384(1–2):57–63.

    Article  PubMed  Google Scholar 

  18. Zhou G, Zhai Y, Cui Y, Qiu W, Yang H, Zhang X, et al. Functional polymorphisms and haplotypes in the promoter of the MMP2 gene are associated with risk of nasopharyngeal carcinoma. Hum Mutat. 2007;28(11):1091–7.

    Article  CAS  PubMed  Google Scholar 

  19. Shao JY, Cao Y, Miao XP, Huang MY, Deng L, Hao JJ, et al. A single nucleotide polymorphism in the matrix metalloproteinase 2 promoter is closely associated with high risk of nasopharyngeal carcinoma in Cantonese from southern China. Chin J Cancer. 2011;30(9):620–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Xiao WW, Huang SM, Han F, Wu SX, Lu LX, Lin CG, et al. Local control, survival, and late toxicities of locally advanced nasopharyngeal carcinoma treated by simultaneous modulated accelerated radiotherapy combined with cisplatin concurrent chemotherapy: long-term results of a phase 2 study. Cancer. 2011;117(9):1874–83.

    Article  CAS  PubMed  Google Scholar 

  21. Ma J, Mai HQ, Hong MH, Cui NJ, Lu TX, Lu LX, et al. Is the 1997 AJCC staging system for nasopharyngeal carcinoma prognostically useful for Chinese patient populations? Int J Radiat Oncol Biol Phys. 2001;50(5):1181–9.

    Article  CAS  PubMed  Google Scholar 

  22. Nishioka Y, Sagae S, Nishikawa A, Ishioka S, Kudo R. A relationship between Matrix metalloproteinase-1 (MMP-1) promoter polymorphism and cervical cancer progression. Cancer Lett. 2003;200(1):49–55.

    Article  CAS  PubMed  Google Scholar 

  23. Matsumura S, Oue N, Nakayama H, Kitadai Y, Yoshida K, Yamaguchi Y, et al. A single nucleotide polymorphism in the MMP-9 promoter affects tumor progression and invasive phenotype of gastric cancer. J Cancer Res Clin Oncol. 2005;131(1):19–25.

    Article  CAS  PubMed  Google Scholar 

  24. Li Y, Jin X, Kang S, Wang Y, Du H, Zhang J, et al. Polymorphisms in the promoter regions of the matrix metalloproteinases-1, -3, -7, and -9 and the risk of epithelial ovarian cancer in China. Gynecol Oncol. 2006;101(1):92–6.

    Article  CAS  PubMed  Google Scholar 

  25. Holliday DL, Hughes S, Shaw JA, Walker RA, Jones JL. Intrinsic genetic characteristics determine tumor-modifying capacity of fibroblasts: matrix metalloproteinase-3 5A/5A genotype enhances breast cancer cell invasion. Breast Cancer Res. 2007;9(5):R67.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Sauter W, Rosenberger A, Beckmann L, Kropp S, Mittelstrass K, Timofeeva M, et al. Matrix metalloproteinase 1 (MMP1) is associated with early-onset lung cancer. Cancer Epidem Biomar. 2008;17(5):1127–35.

    Article  CAS  Google Scholar 

  27. Shimizu Y, Kondo S, Shirai A, Furukawa M, Yoshizaki T. A single nucleotide polymorphism in the matrix metalloproteinase-1 and interleukin-8 gene promoter predicts poor prognosis in tongue cancer. Auris Nasus Larynx. 2008;35(3):381–9.

    Article  PubMed  Google Scholar 

  28. Tang Y, Zhu J, Chen L, Zhang S, Lin J. Associations of matrix metalloproteinase-9 protein polymorphisms with lymph node metastasis but not invasion of gastric cancer. Clin Cancer Res. 2008;14(9):2870–7.

    Article  CAS  PubMed  Google Scholar 

  29. Khanna M, Cao W, Zirvi M, Paty P, Barany F. Ligase detection reaction for identification of low abundance mutations. Clin Biochem. 1999;32(4):287–90.

    Article  CAS  PubMed  Google Scholar 

  30. Consolandi C, Busti E, Pera C, Delfino L, Ferrara GB, Bordoni R, et al. Detection of HLA polymorphisms by ligase detection reaction and a universal array format: a pilot study for low resolution genotyping. Hum Immunol. 2003;64(1):168–78.

    Article  CAS  PubMed  Google Scholar 

  31. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer. 1977;35(1):1–39.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21(2):263–5.

    Article  CAS  PubMed  Google Scholar 

  33. Stephens M, Donnelly P. A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet. 2003;73(5):1162–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Fallin D, Cohen A, Essioux L, Chumakov I, Blumenfeld M, Cohen D, et al. Genetic analysis of case/control data using estimated haplotype frequencies: application to APOE locus variation and Alzheimer’s disease. Genome Res. 2001;11(1):143–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Graziano F, Ruzzo A, Santini D, Humar B, Tonini G, Catalano V, et al. Prognostic role of interleukin-1beta gene and interleukin-1 receptor antagonist gene polymorphisms in patients with advanced gastric cancer. J Clin Oncol. 2005;23(10):2339–45.

    Article  CAS  PubMed  Google Scholar 

  36. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B. 1995;57:289–300.

    Google Scholar 

  37. Wilson CL, Matrisian LM. Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions. Int J Biochem Cell Biol. 1996;28(2):123–36.

    Article  CAS  PubMed  Google Scholar 

  38. Jordan RC, Macabeo-Ong M, Shiboski CH, Dekker N, Ginzinger DG, Wong DT, et al. Overexpression of matrix metalloproteinase-1 and -9 mRNA is associated with progression of oral dysplasia to cancer. Clin Cancer Res. 2004;10(19):6460–5.

    Article  CAS  PubMed  Google Scholar 

  39. Aglund K, Rauvala M, Puistola U, Angstrom T, Turpeenniemi-Hujanen T, Zackrisson B, et al. Gelatinases A and B (MMP-2 and MMP-9) in endometrial cancer-MMP-9 correlates to the grade and the stage. Gynecol Oncol. 2004;94(3):699–704.

    Article  CAS  PubMed  Google Scholar 

  40. Liu Z, Li L, Yang Z, Luo W, Li X, Yang H, et al. Increased expression of MMP9 is correlated with poor prognosis of nasopharyngeal carcinoma. BMC Cancer. 2010;10:270.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Han YJ, Kim HN, Yoon JK, Yi SY, Moon HS, Ahn JJ, et al. Haplotype analysis of the matrix metalloproteinase-9 gene associated with advanced-stage endometriosis. Fertil Steril. 2009;91(6):2324–30.

    Article  CAS  PubMed  Google Scholar 

  42. Wu J, Zhang L, Luo H, Zhu Z, Zhang C, Hou Y. Association of matrix metalloproteinases-9 gene polymorphisms with genetic susceptibility to esophageal squamous cell carcinoma. DNA Cell Biol. 2008;27(10):553–7.

    Article  CAS  PubMed  Google Scholar 

  43. Srivastava P, Mandhani A, Kapoor R, Mittal RD. Role of MMP-3 and MMP-9 and their haplotypes in risk of bladder cancer in North Indian cohort. Ann Surg Oncol. 2010;17(11):3068–75.

    Article  PubMed  Google Scholar 

  44. Bode W, Fernandez-Catalan C, Tschesche H, Grams F, Nagase H, Maskos K. Structural properties of matrix metalloproteinases. Cell Mol Life Sci. 1999;55(4):639–52.

    Article  CAS  PubMed  Google Scholar 

  45. Zhang B, Henney A, Eriksson P, Hamsten A, Watkins H, Ye S. Genetic variation at the matrix metalloproteinase-9 locus on chromosome 20q12.2-13.1. Hum Genet. 1999;105(5):418–23.

    Article  CAS  PubMed  Google Scholar 

  46. Awakura Y, Ito N, Nakamura E, Takahashi T, Kotani H, Mikami Y, et al. Matrix metalloproteinase-9 polymorphisms and renal cell carcinoma in a Japanese population. Cancer Lett. 2006;241(1):59–63.

    Article  CAS  PubMed  Google Scholar 

  47. Lei H, Hemminki K, Altieri A, Johansson R, Enquist K, Hallmans G, et al. Promoter polymorphisms in matrix metalloproteinases and their inhibitors: few associations with breast cancer susceptibility and progression. Breast Cancer Res Treat. 2007;103(1):61–9.

    Article  CAS  PubMed  Google Scholar 

  48. Zhang B, Ye S, Herrmann SM, Eriksson P, de Maat M, Evans A, et al. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation. 1999;99(14):1788–94.

    Article  CAS  PubMed  Google Scholar 

  49. Wang Y, Fang S, Wei L, Wang R, Jin X, Wen D, et al. No association between the C-1562T polymorphism in the promoter of matrix metalloproteinase-9 gene and non-small cell lung carcinoma. Lung Cancer. 2005;49(2):155–61.

    Article  PubMed  Google Scholar 

  50. Przybylowska K, Kluczna A, Zadrozny M, Krawczyk T, Kulig A, Rykala J, et al. Polymorphisms of the promoter regions of matrix metalloproteinases genes MMP-1 and MMP-9 in breast cancer. Breast Cancer Res Treat. 2006;95(1):65–72.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Prof. Qing Liu and Ying Guo for statistical assistance and the Tumor Resources Bank of Sun Yat-sen University Cancer Center for providing blood samples. This research was supported by grants from the National Natural Science Foundation of China (No.: 30600755; No.: 81072226), the 863 Project (No.: 2012AA02A501), the Sci-Tech Project Foundation of Guangdong Province (No.: 2011B080701034), the Sci-Tech Project Foundation of Guangzhou City (No.: 2011J4300100), and Fundamental Research Funds for the Central Universities.

Conflict of interest

None declared.

Author information

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China

    Huai Liu, Pei-Yu Huang, Lin-Quan Tang, Qiu-Yan Chen, Ying Zhang, Lu Zhang, Ling Guo, Dong-Hua Luo, Hao-Yuan Mo, Yan-Qun Xiang, Fang Qiu, Rui Sun, Ming-Yuan Chen, Yi-Jun Hua, Xing Lv, Lin Wang, Chong Zhao, Xiang Guo, Ka-Jia Cao, Chao-Nan Qian, Ming-Huang Hong & Hai-Qiang Mai

  2. Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China

    Huai Liu, Pei-Yu Huang, Lin-Quan Tang, Qiu-Yan Chen, Lu Zhang, Ling Guo, Dong-Hua Luo, Hao-Yuan Mo, Yan-Qun Xiang, Fang Qiu, Rui Sun, Ming-Yuan Chen, Yi-Jun Hua, Xing Lv, Lin Wang, Xiang Guo, Ka-Jia Cao, Chao-Nan Qian & Hai-Qiang Mai

  3. Tumor Resources Bank, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China

    Ying Zhang

  4. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China

    Chong Zhao

  5. GCP Center, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China

    Ming-Huang Hong

Authors
  1. Huai Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pei-Yu Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lin-Quan Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qiu-Yan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ling Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dong-Hua Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hao-Yuan Mo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yan-Qun Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Fang Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Rui Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ming-Yuan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yi-Jun Hua
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Xing Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Lin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Chong Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Xiang Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Ka-Jia Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Chao-Nan Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Ming-Huang Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Hai-Qiang Mai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ming-Huang Hong or Hai-Qiang Mai.

Additional information

Huai Liu, Pei-Yu Huang, and Lin-Quan Tang contributed equally to this article.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, H., Huang, PY., Tang, LQ. et al. Functional polymorphisms of matrix metalloproteinase-9 and survival in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy. Med Oncol 30, 685 (2013). https://doi.org/10.1007/s12032-013-0685-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-013-0685-6

Keywords

Search

Navigation