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Published in:

01-02-2019

Multimodal techniques failed to detect cytomegalovirus in human glioblastoma samples

Authors: Marie-Pierre Loit, Homa Adle-Biassette, Schahrazed Bouazza, Marie-Christine Mazeron, Philippe Manivet, Jacqueline Lehmann-Che, Natacha Teissier, Emmanuel Mandonnet, Jean-Michel Molina

Published in: Journal of NeuroVirology | Issue 1/2019

Abstract

The role of the human cytomegalovirus (HCMV) in gliomagenesis is largely debated. Contradictory data exist regarding the sensitivity and specificity of HCMV detection techniques, including immunohistochemistry (IHC), in situ hybridization (ISH), and RNA and DNA sequencing. The aim of this study is to detect HCMV in glioblastoma (GBM) tumor samples using IHC, ISH, and real-time PCR (qPCR), as well as to correlate the findings with serological status and HCMV DNA load in blood. Forty-seven patients with histopathological diagnosis of GBM and HCMV serological status were retrospectively reviewed. HCMV DNA quantification in whole blood was performed in 31 patients. The detection of HCMV in tumor samples was performed using IHC in 42 cases, ISH in 10 cases, and qPCR in 29 cases. All but two patients were taking high steroid doses at the time of biological testing. HCMV seroprevalence was 68%. Active infection with HCMV DNA detected in blood was diagnosed in 6 out of 21 (28%) seropositive patients. HCMV was not detected in GBM samples using IHC or ISH, while qPCR was positive in one case (also positive for blood HCMV DNA). These data do not support a crucial role of HCMV in GBM tumorigenesis. HCMV might be reactivated in GBM patients, due to steroid treatment.

Adle-Biassette H, Grassi J, Verney C, Walker F, Choudat L, Hénin D (2007) The importance of controls in immunohistochemistry: how to validate an antibody, from research to diagnosis. Ann Pathol 27:16–26CrossRefPubMed

Baumgarten P, Michaelis M, Rothweiler F, Starzetz T, Rabenau HF, Berger A, Jennewein L, Braczynski AK, Franz K, Seifert V, Steinbach JP, Allwinn R, Mittelbronn M, Cinatl J (2014) Human cytomegalovirus infection in tumor cells of the nervous system is not detectable with standardized pathologico-virological diagnostics. Neuro Oncol 16:1469–1477. https://doi.org/10.1093/neuonc/nou167 CrossRefPubMedPubMedCentral

Cannon MJ, Schmid DS, Hyde TB (2010) Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol 20:202–213. https://doi.org/10.1002/rmv.655 CrossRefPubMed

Chen H-P, Jiang J-K, Chan C-H et al (2015) Genetic polymorphisms of the human cytomegalovirus UL144 gene in colorectal cancer and its association with clinical outcome. J Gen Virol 96:3613–3623. https://doi.org/10.1099/jgv.0.000308 CrossRefPubMed

Cobbs C (2014) Response to “human cytomegalovirus infection in tumor cells of the nervous system is not detectable with standardized pathologico-virological diagnostics.”. Neuro Oncol 16:1435–1436. https://doi.org/10.1093/neuonc/nou295 CrossRefPubMedPubMedCentral

Cobbs CS, Harkins L, Samanta M, Gillespie GY, Bharara S, King PH, Nabors LB, Cobbs CG, Britt WJ (2002) Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res 62:3347–3350PubMed

Cosset É, Petty TJ, Dutoit V, Cordey S, Padioleau I, Otten-Hernandez P, Farinelli L, Kaiser L, Bruyère-Cerdan P, Tirefort D, Amar el-Dusouqui S, Nayernia Z, Krause KH, Zdobnov EM, Dietrich PY, Rigal E, Preynat-Seauve O (2014) Comprehensive metagenomic analysis of glioblastoma reveals absence of known virus despite antiviral-like type I interferon gene response. Int J Cancer 135:1381–1389. https://doi.org/10.1002/ijc.28670 CrossRefPubMedPubMedCentral

Crough T, Khanna R (2009) Immunobiology of human cytomegalovirus: from bench to bedside. Clin Microbiol Rev 22:76–98. https://doi.org/10.1128/CMR.00034-08 CrossRefPubMedPubMedCentral

Dziurzynski K, Chang SM, Heimberger AB, Kalejta RF, McGregor Dallas SR, Smit M, Soroceanu L, Cobbs CS, the HCMV and Gliomas Symposium (2012) Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol 14:246–255. https://doi.org/10.1093/neuonc/nor227 CrossRefPubMedPubMedCentral

Garcia-Martinez A, Alenda C, Irles E, Ochoa E, Quintanar T, Rodriguez-Lescure A, Soto JL, Barbera VM (2017) Lack of cytomegalovirus detection in human glioma. Virol J 14:216. https://doi.org/10.1186/s12985-017-0885-3 CrossRefPubMedPubMedCentral

Goerig NL, Frey B, Überla K, Gaipl U, Fietkau R (2017) A clinician’s plea to test glioma patients for CMV. Neuro Oncol 19:1282–1283. https://doi.org/10.1093/neuonc/nox080 CrossRefPubMedPubMedCentral

Hochhalter CB, Carr C, O’Neill BE, Ware ML, Strong MJ (2017) The association between human cytomegalovirus and glioblastomas: a review. Neuroimmunol Neuroinflammation 4:96. https://doi.org/10.20517/2347-8659.2017.10 CrossRef

Holdhoff M, Guner G, Rodriguez FJ, Hicks JL, Zheng Q, Forman MS, Ye X, Grossman SA, Meeker AK, Heaphy CM, Eberhart CG, de Marzo AM, Arav-Boger R (2017) Absence of cytomegalovirus in glioblastoma and other high-grade gliomas by real-time PCR, immunohistochemistry, and in situ hybridization. Clin Cancer Res 23:3150–3157. https://doi.org/10.1158/1078-0432.CCR-16-1490 CrossRefPubMed

Johnson DR, O’Neill BP (2012) Glioblastoma survival in the United States before and during the temozolomide era. J Neuro-Oncol 107:359–364. https://doi.org/10.1007/s11060-011-0749-4 CrossRef

Johnson TS, Abrams ZB, Mo X, Zhang Y, Huang K (2017) Lack of human cytomegalovirus expression in single cells from glioblastoma tumors and cell lines. J Neuro-Oncol 23:671–678. https://doi.org/10.1007/s13365-017-0543-y CrossRef

Khoury JD, Tannir NM, Williams MD, Chen Y, Yao H, Zhang J, Thompson EJ, the TCGA Network, Meric-Bernstam F, Medeiros LJ, Weinstein JN, Su X (2013) Landscape of DNA virus associations across human malignant cancers: analysis of 3,775 cases using RNA-Seq. J Virol 87:8916–8926. https://doi.org/10.1128/JVI.00340-13 CrossRefPubMedPubMedCentral

Lau SK, Chen Y-Y, Chen W-G, Diamond DJ, Mamelak AN, Zaia JA, Weiss LM (2005) Lack of association of cytomegalovirus with human brain tumors. Mod Pathol 18:838–843. https://doi.org/10.1038/modpathol.3800352 CrossRefPubMed

Lin C-TM, Leibovitch EC, Almira-Suarez MI, Jacobson S (2016) Human herpesvirus multiplex ddPCR detection in brain tissue from low- and high-grade astrocytoma cases and controls. Infect Agent Cancer 11:32. https://doi.org/10.1186/s13027-016-0081-x CrossRefPubMedPubMedCentral

Ljungman P (2014) The role of cytomegalovirus serostatus on outcome of hematopoietic stem cell transplantation. Curr Opin Hematol 21:466–469. https://doi.org/10.1097/MOH.0000000000000085 CrossRefPubMed

Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol (Berl) 131:803–820. https://doi.org/10.1007/s00401-016-1545-1 CrossRef

Löwenberg M, Stahn C, Hommes DW, Buttgereit F (2008) Novel insights into mechanisms of glucocorticoid action and the development of new glucocorticoid receptor ligands. Steroids 73:1025–1029. https://doi.org/10.1016/j.steroids.2007.12.002 CrossRefPubMed

Michaelis M, Mittelbronn M, Cinatl J (2015) Towards an unbiased, collaborative effort to reach evidence about the presence of human cytomegalovirus in glioblastoma (and other tumors). Neuro Oncol 17:1039. https://doi.org/10.1093/neuonc/nov048 CrossRefPubMedPubMedCentral

Richardson AK, Currie MJ, Robinson BA, Morrin H, Phung Y, Pearson JF, Anderson TP, Potter JD, Walker LC (2015) Cytomegalovirus and Epstein-Barr virus in breast cancer. PLoS One 10:e0118989. https://doi.org/10.1371/journal.pone.0118989 CrossRefPubMedPubMedCentral

Saper CB (2005) An open letter to our readers on the use of antibodies. J Comp Neurol 493:477–478. https://doi.org/10.1002/cne.20839 CrossRefPubMed

Saper CB, Sawchenko PE (2003) Magic peptides, magic antibodies: guidelines for appropriate controls for immunohistochemistry. J Comp Neurol 465:161–163. https://doi.org/10.1002/cne.10858 CrossRefPubMed

Solomon IH, Ramkissoon SH, Milner DA, Folkerth RD (2014) Cytomegalovirus and glioblastoma: a review of evidence for their association and indications for testing and treatment. J Neuropathol Exp Neurol 73:994–998. https://doi.org/10.1097/NEN.0000000000000125 CrossRefPubMed

Staras SAS, Dollard SC, Radford KW, Flanders WD, Pass RF, Cannon MJ (2006) Seroprevalence of cytomegalovirus infection in the United States, 1988-1994. Clin Infect Dis 43:1143–1151. https://doi.org/10.1086/508173 CrossRefPubMed

Strong MJ, Blanchard E, Lin Z, Morris CA, Baddoo M, Taylor CM, Ware ML, Flemington EK (2016) A comprehensive next generation sequencing-based virome assessment in brain tissue suggests no major virus - tumor association. Acta Neuropathol Commun 4:71. https://doi.org/10.1186/s40478-016-0338-z CrossRefPubMedPubMedCentral

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. https://doi.org/10.1056/NEJMoa043330 CrossRefPubMed

Taha MS, Abdalhamid BA, El-Badawy SA et al (2016) Expression of cytomegalovirus in glioblastoma multiforme: myth or reality? Br J Neurosurg 30:307–312. https://doi.org/10.3109/02688697.2015.1119241 CrossRefPubMed

Tang K-W, Alaei-Mahabadi B, Samuelsson T, Lindh M, Larsson E (2013) The landscape of viral expression and host gene fusion and adaptation in human cancer. Nat Commun 4:2513. https://doi.org/10.1038/ncomms3513 CrossRefPubMed

Tang K-W, Hellstrand K, Larsson E (2015) Absence of cytomegalovirus in high-coverage DNA sequencing of human glioblastoma multiforme. Int J Cancer 136:977–981. https://doi.org/10.1002/ijc.29042 CrossRefPubMed

Teissier N, Delezoide A-L, Mas A-E, Khung-Savatovsky S, Bessières B, Nardelli J, Vauloup-Fellous C, Picone O, Houhou N, Oury JF, van den Abbeele T, Gressens P, Adle-Biassette H (2011) Inner ear lesions in congenital cytomegalovirus infection of human fetuses. Acta Neuropathol (Berl) 122:763–774. https://doi.org/10.1007/s00401-011-0895-y CrossRef

Teissier N, Fallet-Bianco C, Delezoide A-L, Laquerrière A, Marcorelles P, Khung-Savatovsky S, Nardelli J, Cipriani S, Csaba Z, Picone O, Golden JA, van den Abbeele T, Gressens P, Adle-Biassette H (2014) Cytomegalovirus-induced brain malformations in fetuses. J Neuropathol Exp Neurol 73:143–158. https://doi.org/10.1097/NEN.0000000000000038 CrossRefPubMed

Ward JM (2004) Controls for immunohistochemistry: is “brown” good enough? Toxicol Pathol 32:273–274. https://doi.org/10.1080/01926230490457585 CrossRefPubMed

Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507. https://doi.org/10.1056/NEJMra0708126 CrossRefPubMed

Yamashita Y, Ito Y, Isomura H, Takemura N, Okamoto A, Motomura K, Tsujiuchi T, Natsume A, Wakabayashi T, Toyokuni S, Tsurumi T (2014) Lack of presence of the human cytomegalovirus in human glioblastoma. Mod Pathol 27:922–929. https://doi.org/10.1038/modpathol.2013.219 CrossRefPubMed

Title: Multimodal techniques failed to detect cytomegalovirus in human glioblastoma samples
Authors: Marie-Pierre Loit
Homa Adle-Biassette
Schahrazed Bouazza
Marie-Christine Mazeron
Philippe Manivet
Jacqueline Lehmann-Che
Natacha Teissier
Emmanuel Mandonnet
Jean-Michel Molina
Publication date: 01-02-2019
Publisher: Springer International Publishing
Published in: Journal of NeuroVirology / Issue 1/2019
Print ISSN: 1355-0284
Electronic ISSN: 1538-2443
DOI: https://doi.org/10.1007/s13365-018-0683-8

At a glance: The STEP trials

Springer Medicine

Multimodal techniques failed to detect cytomegalovirus in human glioblastoma samples

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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