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Decreased human leukocyte antigen A*02:01 frequency is associated with risk of glioma and existence of human cytomegalovirus: a case–control study in Northern China

Cancer Immunology, Immunotherapy volume 66, pages 1265–1273 (2017)Cite this article

Abstract

Background

Human leukocyte antigens (HLAs) play an important role in host defense against viral infection and tumorigenesis. Human cytomegalovirus (HCMV) has been linked to glioma development. This study investigated the relationship between HLA distribution, presence of HCMV, and glioma development in a Han Chinese population.

Methods

The study population included 150 glioma patients and 150 tumor-free brain injury control subjects (control-A) matched according to geography, ethnicity, age, and gender. HLA allele frequency was compared between the two groups using peripheral blood samples by PCR sequence-based typing. These data were also compared with HLA frequencies obtained from a Northern Chinese Han population database (control-B). HCMV DNA was detected in the peripheral blood of glioma patients and control group-A by nested PCR. The expression of HCMV proteins IE1-72 and pp65 in tumor tissues was evaluated by immunohistochemistry.

Results

The frequency of HLA-A*02:01 was decreased in glioma patients as compared to control group-A and -B (P < 0.001 and P = 0.001, respectively). The age/sex-adjusted odds ratio for HLA-A*02:01 positivity vs. negativity was 0.392 (95% confidence interval 0.225–0.683). HCMV was more frequently detected in the peripheral blood and tumor tissue of HLA-A*02:01-negative glioma patients. HLA-A*02:01 and HCMV were not associated with overall survival.

Conclusion

There is a correlation between decreased HLA-A*0201 allele frequency and glioma susceptibility.

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Abbreviations

CI:

Confidence interval

GBM:

Glioblastoma

HCMV:

Human cytomegalovirus

HLA:

Human leukocyte antigen

IDH:

Isocitrate dehydrogenase

IgG:

Immunoglobulin G

IgM:

Immunoglobulin M

MGMT:

O-6 methylguanine DNA methyltransferase

OR:

Odds ratio

OS:

Overall survival

References

  1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    CAS  Article  PubMed  Google Scholar 

  2. Baumgarten P, Michaelis M, Rothweiler F, Starzetz T, Rabenau HF et al (2014) Human cytomegalovirus infection in tumor cells of the nervous system is not detectable with standardized pathologico-virological diagnostics. Neuro Oncol 16:1469–1477

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Strong MJ, Blanchard E 4th, Lin Z, Morris CA, Baddoo M et al (2016) A comprehensive next generation sequencing-based virome assessment in brain tissue suggests no major virus—tumor association. Acta Neuropathol Commun 4:71

    Article  PubMed  PubMed Central  Google Scholar 

  4. Mitchell DA, Xie W, Schmittling R, Learn C, Friedman A et al (2008) Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol 10:10–18

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ding D, Han S, Wang Z, Guo Z, Wu A (2014) Does the existence of HCMV components predict poor prognosis in glioma. J Neurooncol 116:515–522

    CAS  Article  PubMed  Google Scholar 

  6. Dziurzynski K, Chang SM, Heimberger AB, Kalejta RF, McGregor DSR et al (2012) Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol 14:246–255

    Article  PubMed  PubMed Central  Google Scholar 

  7. Mohammad AA, Rahbar A, Lui WO, Davoudi B, Catrina A et al (2014) Detection of circulating hcmv-miR-UL112-3p in patients with glioblastoma, rheumatoid arthritis, diabetes mellitus and healthy controls. PLoS One 9:e113740

    Article  PubMed  PubMed Central  Google Scholar 

  8. dos Santos CJ, Stangherlin LM, Figueiredo EG, Correa C, Teixeira MJ, da Silva MC (2014) High prevalence of HCMV and viral load in tumor tissues and peripheral blood of glioblastoma multiforme patients. J Med Virol 86:1953–1961

    Article  PubMed  Google Scholar 

  9. Fajfr M, Stepanova V (2013) Cytomegalovirus and its relationship to chronic inflammatory bowel diseases and tumors. Klin Mikrobiol Infekc Lek 19:103–106

    CAS  PubMed  Google Scholar 

  10. Cobbs CS (2013) Cytomegalovirus and brain tumor: epidemiology, biology and therapeutic aspects. Curr Opin Oncol 25:682–688

    Article  PubMed  Google Scholar 

  11. Price RL, Song J, Bingmer K, Kim TH, Yi JY et al (2013) Cytomegalovirus contributes to glioblastoma in the context of tumor suppressor mutations. Cancer Res 73:3441–3450

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Zhang HG, Pang XW, Shang XY, Xing Q, Chen WF (2003) Functional supertype of HLA-A2 in the presentation of Flu matrix p58–66 to induce CD8+ T-cell response in a Northern Chinese population. Tissue Antigens 62:285–295

    CAS  Article  PubMed  Google Scholar 

  13. La Torre D, Maugeri R, Angileri FF, Pezzino G, Conti A et al (2009) Human leukocyte antigen frequency in human high-grade gliomas: a case–control study in Sicily. Neurosurgery 64:1082–1088 (discussion 1088–1089)

    Article  PubMed  Google Scholar 

  14. Hou TY, Chen HC, Chen CH, Chang DM, Liu FC, Lai JH (2007) Usefulness of human leucocyte antigen-B27 subtypes in predicting ankylosing spondylitis: Taiwan experience. Intern Med J 37:749–752

    PubMed  Google Scholar 

  15. Ballerini C, Guerini FR, Rombola G, Rosati E, Massacesi L et al (2004) HLA-multiple sclerosis association in continental Italy and correlation with disease prevalence in Europe. J Neuroimmunol 150:178–185

    CAS  Article  PubMed  Google Scholar 

  16. Gonzalez-Gay MA, Garcia-Porrua C, Hajeer AH (2002) Influence of human leukocyte antigen-DRB1 on the susceptibility and severity of rheumatoid arthritis. Semin Arthritis Rheum 31:355–360

    CAS  Article  PubMed  Google Scholar 

  17. Luongo V, Pirozzi G, Caraco C, Errico S, de Angelis F et al (2004) HLA allele frequency and clinical outcome in Italian patients with cutaneous melanoma. Tissue Antigens 64:84–87

    CAS  Article  PubMed  Google Scholar 

  18. Ohtani M, Azuma T, Yamazaki S, Yamakawa A, Ito Y et al (2003) Association of the HLA-DRB1 gene locus with gastric adenocarcinoma in Japan. Dig Liver Dis 35:468–472

    CAS  Article  PubMed  Google Scholar 

  19. Younger AR, Amria S, Jeffrey WA, Mahdy AE, Goldstein OG et al (2008) HLA class II antigen presentation by prostate cancer cells. Prostate Cancer Prostatic Dis 11:334–341

    CAS  Article  PubMed  Google Scholar 

  20. Song W, Ruder AM, Hu L, Li Y, Ni R et al (2009) Genetic epidemiology of glioblastoma multiforme: confirmatory and new findings from analyses of human leukocyte antigen alleles and motifs. PLoS One 4:e7157

    Article  PubMed  PubMed Central  Google Scholar 

  21. Guerini FR, Agliardi C, Zanzottera M, Delbue S, Pagani E et al (2006) Human leukocyte antigen distribution analysis in North Italian brain Glioma patients: an association with HLA-DRB1*14. J Neurooncol 77:213–217

    CAS  Article  PubMed  Google Scholar 

  22. Tang J, Shao W, Dorak MT, Li Y, Miike R et al (2005) Positive and negative associations of human leukocyte antigen variants with the onset and prognosis of adult glioblastoma multiforme. Cancer Epidemiol Biomark Prev 14:2040–2044

    CAS  Article  Google Scholar 

  23. Bassig BA, Inskip PD, Burdette L, Shapiro WR, Selker RG et al (2011) Selected human leukocyte antigen class II polymorphisms and risk of adult glioma. J Neuroimmunol 233:185–191

    CAS  Article  PubMed  Google Scholar 

  24. Krausa P, Brywka M 3rd, Savage D, Hui KM, Bunce M et al (1995) Genetic polymorphism within HLA-A*02: significant allelic variation revealed in different populations. Tissue Antigens 45:223–231

    CAS  Article  PubMed  Google Scholar 

  25. Liang B, Zhu L, Liang Z, Weng X, Lu X et al (2006) A simplified PCR-SSP method for HLA-A2 subtype in a population of Wuhan, China. Cell Mol Immunol 3:453–458

    CAS  PubMed  Google Scholar 

  26. Yang G, Deng YJ, Hu SN, Wu DY, Li SB et al (2006) HLA-A, -B, and -DRB1 polymorphism defined by sequence-based typing of the Han population in Northern China. Tissue Antigens 67:146–152

    CAS  Article  PubMed  Google Scholar 

  27. Deng Z, Wang D, Xu Y, Gao S, Zhou H et al (2010) HLA-C polymorphisms and PCR dropout in exons 2 and 3 of the Cw*0706 allele in sequence-based typing for unrelated Chinese marrow donors. Hum Immunol 71:577–581

    CAS  Article  PubMed  Google Scholar 

  28. Scheurer ME, Bondy ML, Aldape KD, Albrecht T, El-Zein R (2008) Detection of human cytomegalovirus in different histological types of gliomas. Acta Neuropathol 116:79–86

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Cobbs CS, Matlaf L, Harkins LE (2014) Methods for the detection of cytomegalovirus in glioblastoma cells and tissues. Methods Mol Biol 1119:165–196

    CAS  Article  PubMed  Google Scholar 

  30. Sjostrom S, Hjalmars U, Juto P, Wadell G, Hallmans G et al (2011) Human immunoglobulin G levels of viruses and associated glioma risk. Cancer Causes Control 22:1259–1266

    Article  PubMed  PubMed Central  Google Scholar 

  31. Amirian ES, Marquez-Do D, Bondy ML, Scheurer ME (2013) Anti-human-cytomegalovirus immunoglobulin G levels in glioma risk and prognosis. Cancer Med 2:57–62

    Article  PubMed  Google Scholar 

  32. Soroceanu L, Cobbs CS (2011) Is HCMV a tumor promoter. Virus Res 157:193–203

    CAS  Article  PubMed  Google Scholar 

  33. Hambardzumyan D, Gutmann DH, Kettenmann H (2016) The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci 19:20–27

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Okano F, Storkus WJ, Chambers WH, Pollack IF, Okada H (2002) Identification of a novel HLA-A*0201-restricted, cytotoxic T lymphocyte epitope in a human glioma-associated antigen, interleukin 13 receptor alpha2 chain. Clin Cancer Res 8:2851–2855

    CAS  PubMed  Google Scholar 

  35. Ji J, Judkowski VA, Liu G, Wang H, Bunying A et al (2014) Identification of novel human leukocyte antigen-A*0201-restricted, cytotoxic T lymphocyte epitopes on CD133 for cancer stem cell immunotherapy. Stem Cells Transl Med 3:356–364

    CAS  Article  PubMed  Google Scholar 

  36. Myers CE, Hanavan P, Antwi K, Mahadevan D, Nadeem AJ et al (2011) CTL recognition of a novel HLA-A*0201-binding peptide derived from glioblastoma multiforme tumor cells. Cancer Immunol Immunother 60:1319–1332

    CAS  Article  PubMed  Google Scholar 

  37. Frigerio S, Ciusani E, Pozzi A, Silvani A, Salmaggi A, Boiardi A (1999) Tumor necrosis factor microsatellite polymorphisms in Italian glioblastoma patients. Cancer Genet Cytogenet 109:172–174

    CAS  Article  PubMed  Google Scholar 

  38. Li R, Zhao Y, Fan W, Chen H, Chen Y et al (2011) Possible association between polymorphisms of human vascular endothelial growth factor A gene and susceptibility to glioma in a Chinese population. Int J Cancer 128:166–175

    CAS  Article  PubMed  Google Scholar 

  39. Yin D, Ogawa S, Kawamata N, Tunici P, Finocchiaro G et al (2009) High-resolution genomic copy number profiling of glioblastoma multiforme by single nucleotide polymorphism DNA microarray. Mol Cancer Res 7:665–677

    CAS  Article  PubMed  Google Scholar 

  40. Tenan M, Carrara F, DiDonato S, Finocchiaro G (1995) Absence of mutations and identification of two polymorphisms in the SSCP and sequence analysis of p21CKI gene in malignant gliomas. Int J Cancer 62:115–117

    CAS  Article  PubMed  Google Scholar 

  41. Tussey LG, Matsui M, Rowland-Jones S, Warburton R, Frelinger JA, McMichael A (1994) Analysis of mutant HLA-A2 molecules. Differential effects on peptide binding and CTL recognition. J Immunol 152:1213–1221

    CAS  PubMed  Google Scholar 

  42. Zou Y, Bresnahan W, Taylor RT, Stastny P (2005) Effect of human cytomegalovirus on expression of MHC class I-related chains A. J Immunol 174:3098–3104

    CAS  Article  PubMed  Google Scholar 

  43. Prins RM, Cloughesy TF, Liau LM (2008) Cytomegalovirus immunity after vaccination with autologous glioblastoma lysate. N Engl J Med 359:539–541

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Schuessler A, Smith C, Beagley L, Boyle GM, Rehan S et al (2014) Autologous T-cell therapy for cytomegalovirus as a consolidative treatment for recurrent glioblastoma. Cancer Res 74:3466–3476

    CAS  Article  PubMed  Google Scholar 

  45. Stragliotto G, Rahbar A, Solberg NW, Lilja A, Taher C et al (2013) Effects of valganciclovir as an add-on therapy in patients with cytomegalovirus-positive glioblastoma: a randomized, double-blind, hypothesis-generating study. Int J Cancer 133:1204–1213

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We thank Jingpu Shi at the Department of Clinical Epidemiology, The First Affiliated Hospital of China Medical University, for assistance with statistical and survival analyses.

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Affiliations

  1. Department of Neurosurgery, The First Hospital of China Medical University, Nanjing Street 155, Heping District, Shenyang, 110001, China

    Sheng Han, Jian Deng, Zixun Wang, Huan Liu, Wen Cheng & Anhua Wu

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  1. Sheng Han
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  2. Jian Deng
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  3. Zixun Wang
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  4. Huan Liu
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  5. Wen Cheng
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  6. Anhua Wu
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Correspondence to Anhua Wu.

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Funding

This work was supported by Grants from National Natural Science Foundation of China (Grant Nos. 81472360 and 81402045) and the Science and Technology Department of Liaoning Province (No. 2011225034).

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The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Han, S., Deng, J., Wang, Z. et al. Decreased human leukocyte antigen A*02:01 frequency is associated with risk of glioma and existence of human cytomegalovirus: a case–control study in Northern China. Cancer Immunol Immunother 66, 1265–1273 (2017). https://doi.org/10.1007/s00262-017-2018-7

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  • DOI: https://doi.org/10.1007/s00262-017-2018-7

Keywords

  • Glioma
  • HLA
  • HCMV
  • Immunology
  • Immunotherapy