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Published in: Herpesviridae 1/2012

Open Access 01-12-2012 | Research

Low levels of Human Cytomegalovirus Infection in Glioblastoma multiforme associates with patient survival; -a case-control study

Authors: Afsar Rahbar, Giuseppe Stragliotto, Abiel Orrego, Inti Peredo, Chato Taher, Jan Willems, Cecilia Söderberg-Naucler

Published in: Herpesviridae | Issue 1/2012

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Abstract

Background

Glioblastoma multiforme (GBM) represent the most aggressive brain tumor with a median overall survival of about 12-15 months. Over 90% of GBM tumors have recently been shown to be infected with human cytomegalovirus (HCMV). In this case-control study, we evaluated whether there was an association between the grade of HCMV infection and long-term survival (> 18 months) in GBM patients.

Material and methods

Brain tumor tissue sections from consecutive GBMs patients who survived more than 18 months (n = 40), and an equal number of GBM patients, matched to date of diagnosis and surgery, operated at Karolinska University Hospital in 2000-2005 were selected. HCMV infection grade was determined by estimation of the number of HCMV positive cells (scored negative or grade 1-4) in tumor tissue specimens. Using Chi-Square test and logistic regression analysis, we analyzed whether there was an association between long-term survival and HCMV low-grade infection or other clinical parameters known to be associated with prolonged survival of GBM patients; age under 50 years, radical surgery or low recursive partition analysis (RPA) subclass.

Results

HCMV infection was detected in tumor samples from 79 of 80 patients (99%). Among patients surviving > 18 months, HCMV infection grade 1 in the GBM tumor was predominant. A low grade HCMV infection was found in 19 patients, of these 16 survived > 18 months. Thus, 16 of 40 (40%) GBM patients who lived > 18 months had low-grade HCMV infection while only 3 of 40 (8%) GBM patients who lived < 18 months did (p .0006, Chi-Square test). Multiple logistic regression analyses yielded an odds ratio estimate of 6.604 with 95% confidence interval (1.36-32.1) (p .019) for low grade HCMV after adjustment for RPA class III and IV, radical surgery, age and gamma knife treatment.

Conclusion

In conclusion, we found that low-grade HCMV infection was strongly associated with long-term survival in GBM patients.
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Literature
1.
go back to reference Bergenheim T, et al: Registration on regional basis of patients with primary brain tumors. Regional differences disclosed. Lakartidningen. 2007, 104 (5): 332-338. 340-1PubMed Bergenheim T, et al: Registration on regional basis of patients with primary brain tumors. Regional differences disclosed. Lakartidningen. 2007, 104 (5): 332-338. 340-1PubMed
2.
go back to reference Greenfield's neuropathology. Edited by: Lantos PL VS, KP. 1996, London: Arnold, 6 Greenfield's neuropathology. Edited by: Lantos PL VS, KP. 1996, London: Arnold, 6
3.
go back to reference Gupta M, Djalilvand A, Brat DJ: Clarifying the diffuse gliomas: an update on the morphologic features and markers that discriminate oligodendroglioma from astrocytoma. Am J Clin Pathol. 2005, 124 (5): 755-768. 10.1309/6JNX4PA60TQ5U5VG.CrossRefPubMed Gupta M, Djalilvand A, Brat DJ: Clarifying the diffuse gliomas: an update on the morphologic features and markers that discriminate oligodendroglioma from astrocytoma. Am J Clin Pathol. 2005, 124 (5): 755-768. 10.1309/6JNX4PA60TQ5U5VG.CrossRefPubMed
4.
go back to reference Affronti ML, et al: Overall survival of newly diagnosed glioblastoma patients receiving carmustine wafers followed by radiation and concurrent temozolomide plus rotational multiagent chemotherapy. Cancer. 2009, 115 (15): 3501-3511. 10.1002/cncr.24398.CrossRefPubMed Affronti ML, et al: Overall survival of newly diagnosed glioblastoma patients receiving carmustine wafers followed by radiation and concurrent temozolomide plus rotational multiagent chemotherapy. Cancer. 2009, 115 (15): 3501-3511. 10.1002/cncr.24398.CrossRefPubMed
5.
go back to reference Cobbs CS, et al: Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res. 2002, 62 (12): 3347-3350.PubMed Cobbs CS, et al: Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res. 2002, 62 (12): 3347-3350.PubMed
6.
go back to reference Mitchell DA, et al: Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol. 2008, 10 (1): 10-18. 10.1215/15228517-2007-035.PubMedCentralCrossRefPubMed Mitchell DA, et al: Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol. 2008, 10 (1): 10-18. 10.1215/15228517-2007-035.PubMedCentralCrossRefPubMed
7.
go back to reference Lucas KG, et al: The detection of CMV pp 65 and IE1 in glioblastoma multiforme. J Neurooncol. 2011, 103 (2): 231-238. 10.1007/s11060-010-0383-6.CrossRefPubMed Lucas KG, et al: The detection of CMV pp 65 and IE1 in glioblastoma multiforme. J Neurooncol. 2011, 103 (2): 231-238. 10.1007/s11060-010-0383-6.CrossRefPubMed
8.
go back to reference Taylor-Wiedeman J, et al: Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells. J Gen Virol. 1991, 72 (Pt 9): 2059-2064.CrossRefPubMed Taylor-Wiedeman J, et al: Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells. J Gen Virol. 1991, 72 (Pt 9): 2059-2064.CrossRefPubMed
9.
go back to reference Soderberg-Naucler C, Fish KN, Nelson JA: Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell. 1997, 91 (1): 119-126. 10.1016/S0092-8674(01)80014-3.CrossRefPubMed Soderberg-Naucler C, Fish KN, Nelson JA: Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell. 1997, 91 (1): 119-126. 10.1016/S0092-8674(01)80014-3.CrossRefPubMed
10.
go back to reference Sinclair J: Human cytomegalovirus: Latency and reactivation in the myeloid lineage. J Clin Virol: The Official Publication of the Pan American Society for Clinical Virology. 2008, 41 (3): 180-185. 10.1016/j.jcv.2007.11.014.CrossRef Sinclair J: Human cytomegalovirus: Latency and reactivation in the myeloid lineage. J Clin Virol: The Official Publication of the Pan American Society for Clinical Virology. 2008, 41 (3): 180-185. 10.1016/j.jcv.2007.11.014.CrossRef
11.
go back to reference Cinatl J, et al: Oncomodulatory signals by regulatory proteins encoded by human cytomegalovirus: a novel role for viral infection in tumor progression. FEMS Microbiol Rev. 2004, 28 (1): 59-77. 10.1016/j.femsre.2003.07.005.CrossRefPubMed Cinatl J, et al: Oncomodulatory signals by regulatory proteins encoded by human cytomegalovirus: a novel role for viral infection in tumor progression. FEMS Microbiol Rev. 2004, 28 (1): 59-77. 10.1016/j.femsre.2003.07.005.CrossRefPubMed
12.
go back to reference Boldogh I, AbuBakar S, Albrecht T: Activation of proto-oncogenes: an immediate early event in human cytomegalovirus infection. Science. 1990, 247 (4942): 561-564. 10.1126/science.1689075.CrossRefPubMed Boldogh I, AbuBakar S, Albrecht T: Activation of proto-oncogenes: an immediate early event in human cytomegalovirus infection. Science. 1990, 247 (4942): 561-564. 10.1126/science.1689075.CrossRefPubMed
13.
go back to reference Bresnahan WA, Albrecht T, Thompson EA: The cyclin E promoter is activated by human cytomegalovirus 86-kDa immediate early protein. J Biol Chem. 1998, 273 (34): 22075-22082. 10.1074/jbc.273.34.22075.CrossRefPubMed Bresnahan WA, Albrecht T, Thompson EA: The cyclin E promoter is activated by human cytomegalovirus 86-kDa immediate early protein. J Biol Chem. 1998, 273 (34): 22075-22082. 10.1074/jbc.273.34.22075.CrossRefPubMed
14.
go back to reference Hagemeier C, et al: Functional interaction between the HCMV IE2 transactivator and the retinoblastoma protein. EMBO J. 1994, 13 (12): 2897-2903.PubMedCentralPubMed Hagemeier C, et al: Functional interaction between the HCMV IE2 transactivator and the retinoblastoma protein. EMBO J. 1994, 13 (12): 2897-2903.PubMedCentralPubMed
15.
go back to reference Muganda P, Carrasco R, Qian Q: The human cytomegalovirus IE2 86 kDa protein elevates p53 levels and transactivates the p53 promoter in human fibroblasts. Cell Mol Biol (Noisy-le-Grand). 1998, 44 (2): 321-331. Muganda P, Carrasco R, Qian Q: The human cytomegalovirus IE2 86 kDa protein elevates p53 levels and transactivates the p53 promoter in human fibroblasts. Cell Mol Biol (Noisy-le-Grand). 1998, 44 (2): 321-331.
16.
go back to reference Shen Y, Zhu H, Shenk T: Human cytomagalovirus IE1 and IE2 proteins are mutagenic and mediate "hit-and-run" oncogenic transformation in cooperation with the adenovirus E1A proteins. Proc Natl Acad Sci USA. 1997, 94 (7): 3341-3345. 10.1073/pnas.94.7.3341.PubMedCentralCrossRefPubMed Shen Y, Zhu H, Shenk T: Human cytomagalovirus IE1 and IE2 proteins are mutagenic and mediate "hit-and-run" oncogenic transformation in cooperation with the adenovirus E1A proteins. Proc Natl Acad Sci USA. 1997, 94 (7): 3341-3345. 10.1073/pnas.94.7.3341.PubMedCentralCrossRefPubMed
17.
go back to reference Maussang D, et al: The human cytomegalovirus-encoded chemokine receptor US28 promotes angiogenesis and tumor formation via cyclooxygenase-2. Cancer Res. 2009, 69 (7): 2861-2869. 10.1158/0008-5472.CAN-08-2487.CrossRefPubMed Maussang D, et al: The human cytomegalovirus-encoded chemokine receptor US28 promotes angiogenesis and tumor formation via cyclooxygenase-2. Cancer Res. 2009, 69 (7): 2861-2869. 10.1158/0008-5472.CAN-08-2487.CrossRefPubMed
18.
go back to reference Slinger E, et al: HCMV-encoded chemokine receptor US28 mediates proliferative signaling through the IL-6-STAT3 axis. Sci Signal. 2010, 3 (133): ra58-10.1126/scisignal.2001180.CrossRefPubMed Slinger E, et al: HCMV-encoded chemokine receptor US28 mediates proliferative signaling through the IL-6-STAT3 axis. Sci Signal. 2010, 3 (133): ra58-10.1126/scisignal.2001180.CrossRefPubMed
19.
go back to reference Maussang D, et al: Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis. Proc Natl Acad Sci USA. 2006, 103 (35): 13068-13073. 10.1073/pnas.0604433103.PubMedCentralCrossRefPubMed Maussang D, et al: Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis. Proc Natl Acad Sci USA. 2006, 103 (35): 13068-13073. 10.1073/pnas.0604433103.PubMedCentralCrossRefPubMed
20.
go back to reference Baryawno N, et al: Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J Clin Invest. 2011, 121 (10): 4043-4055. 10.1172/JCI57147.PubMedCentralCrossRefPubMed Baryawno N, et al: Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J Clin Invest. 2011, 121 (10): 4043-4055. 10.1172/JCI57147.PubMedCentralCrossRefPubMed
21.
go back to reference Mirimanoff RO, et al: Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol. 2006, 24 (16): 2563-2569. 10.1200/JCO.2005.04.5963.CrossRefPubMed Mirimanoff RO, et al: Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol. 2006, 24 (16): 2563-2569. 10.1200/JCO.2005.04.5963.CrossRefPubMed
22.
go back to reference Lachin JM: Introduction to sample size determination and power analysis for clinical trials. Control Clin Trials. 1981, 2 (2): 93-113. 10.1016/0197-2456(81)90001-5.CrossRefPubMed Lachin JM: Introduction to sample size determination and power analysis for clinical trials. Control Clin Trials. 1981, 2 (2): 93-113. 10.1016/0197-2456(81)90001-5.CrossRefPubMed
23.
go back to reference Stupp R, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005, 352 (10): 987-996. 10.1056/NEJMoa043330.CrossRefPubMed Stupp R, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005, 352 (10): 987-996. 10.1056/NEJMoa043330.CrossRefPubMed
24.
go back to reference Wen PY, Kesari S: Malignant gliomas in adults. N Engl J Med. 2008, 359 (5): 492-507. 10.1056/NEJMra0708126.CrossRefPubMed Wen PY, Kesari S: Malignant gliomas in adults. N Engl J Med. 2008, 359 (5): 492-507. 10.1056/NEJMra0708126.CrossRefPubMed
25.
go back to reference Shen YH, et al: Human cytomegalovirus inhibits Akt-mediated eNOS activation through upregulating PTEN (phosphatase and tensin homolog deleted on chromosome 10). Cardiovasc Res. 2006, 69 (2): 502-511. 10.1016/j.cardiores.2005.10.007.CrossRefPubMed Shen YH, et al: Human cytomegalovirus inhibits Akt-mediated eNOS activation through upregulating PTEN (phosphatase and tensin homolog deleted on chromosome 10). Cardiovasc Res. 2006, 69 (2): 502-511. 10.1016/j.cardiores.2005.10.007.CrossRefPubMed
26.
go back to reference Straat K, et al: Activation of telomerase by human cytomegalovirus. J Natl Cancer Inst. 2009, 101 (7): 488-497. 10.1093/jnci/djp031.CrossRefPubMed Straat K, et al: Activation of telomerase by human cytomegalovirus. J Natl Cancer Inst. 2009, 101 (7): 488-497. 10.1093/jnci/djp031.CrossRefPubMed
27.
go back to reference Qiu H, et al: Human CMV infection induces 5-lipoxygenase expression and leukotriene B4 production in vascular smooth muscle cells. J Exp Med. 2008, 205 (1): 19-24. 10.1084/jem.20070201.PubMedCentralCrossRefPubMed Qiu H, et al: Human CMV infection induces 5-lipoxygenase expression and leukotriene B4 production in vascular smooth muscle cells. J Exp Med. 2008, 205 (1): 19-24. 10.1084/jem.20070201.PubMedCentralCrossRefPubMed
28.
go back to reference Chen Z, et al: Degradation of p21cip1 in cells productively infected with human cytomegalovirus. J Virol. 2001, 75 (8): 3613-3625. 10.1128/JVI.75.8.3613-3625.2001.PubMedCentralCrossRefPubMed Chen Z, et al: Degradation of p21cip1 in cells productively infected with human cytomegalovirus. J Virol. 2001, 75 (8): 3613-3625. 10.1128/JVI.75.8.3613-3625.2001.PubMedCentralCrossRefPubMed
29.
go back to reference Bongers G, et al: The cytomegalovirus-encoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice. J Clin Invest. 2010, 120 (11): 3969-3978. 10.1172/JCI42563.PubMedCentralCrossRefPubMed Bongers G, et al: The cytomegalovirus-encoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice. J Clin Invest. 2010, 120 (11): 3969-3978. 10.1172/JCI42563.PubMedCentralCrossRefPubMed
30.
go back to reference Soroceanu L, et al: Human Cytomegalovirus US28 Found in Glioblastoma Promotes an Invasive and Angiogenic Phenotype. Cancer Res. 2011 Soroceanu L, et al: Human Cytomegalovirus US28 Found in Glioblastoma Promotes an Invasive and Angiogenic Phenotype. Cancer Res. 2011
31.
go back to reference Dziurzynski K, et al: Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype. Clin Canc Res: An Official Journal of the American Association for Cancer Research. 2011, 17 (14): 4642-4649. 10.1158/1078-0432.CCR-11-0414.CrossRef Dziurzynski K, et al: Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype. Clin Canc Res: An Official Journal of the American Association for Cancer Research. 2011, 17 (14): 4642-4649. 10.1158/1078-0432.CCR-11-0414.CrossRef
32.
go back to reference Kortylewski M, et al: Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med. 2005, 11 (12): 1314-1321. 10.1038/nm1325.CrossRefPubMed Kortylewski M, et al: Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med. 2005, 11 (12): 1314-1321. 10.1038/nm1325.CrossRefPubMed
33.
go back to reference O'Farrell AM, et al: IL-10 inhibits macrophage activation and proliferation by distinct signaling mechanisms: evidence for Stat3-dependent and -independent pathways. EMBO J. 1998, 17 (4): 1006-1018. 10.1093/emboj/17.4.1006.PubMedCentralCrossRefPubMed O'Farrell AM, et al: IL-10 inhibits macrophage activation and proliferation by distinct signaling mechanisms: evidence for Stat3-dependent and -independent pathways. EMBO J. 1998, 17 (4): 1006-1018. 10.1093/emboj/17.4.1006.PubMedCentralCrossRefPubMed
Metadata
Title
Low levels of Human Cytomegalovirus Infection in Glioblastoma multiforme associates with patient survival; -a case-control study
Authors
Afsar Rahbar
Giuseppe Stragliotto
Abiel Orrego
Inti Peredo
Chato Taher
Jan Willems
Cecilia Söderberg-Naucler
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Herpesviridae / Issue 1/2012
Electronic ISSN: 2042-4280
DOI
https://doi.org/10.1186/2042-4280-3-3

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