Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma

Abstract

Human cytomegalovirus (HCMV) has been described to be associated with several human malignancies, though the frequency of detection remains controversial. It is unclear whether HCMV plays an active role in malignant tumor progression or becomes reactivated under pathologic conditions that result in chronic inflammation or immunosuppression. In this study, we report on the investigation of detecting HCMV in the tumors and peripheral blood of patients with newly diagnosed glioblastoma multiforme (GBM). Using immunohistochemistry, in situ hybridization, and polymerase chain reaction amplification of viral DNA, the detection of HCMV was investigated in tumor and blood specimens from patients with GBM as well as in the peripheral blood of normal volunteers and patients undergoing craniotomy for diagnoses other than GBM. We found that a high percentage (>90%) of GBM tumors, not surrounding normal brain, are associated with HCMV nucleic acids and proteins. Furthermore, a significant proportion of patients (80%) with newly diagnosed GBM have detectable HCMV DNA in their peripheral blood, while sero-positive normal donors and other surgical patients did not exhibit detectable virus, suggesting either a systemic reactivation of HCMV within patients with GBM or shedding of viral DNA from infected tumor cells into the periphery. These results confirm the association of HCMV with malignant gliomas and demonstrate that subclinical HCMV viremia (presence of viral DNA in blood without clinical symptoms of infection) is a previously unrecognized disease spectrum in patients with GBM.

Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact

“…26 Other studies have suggested that halted differentiation of neuroprogenitor cells is an early step in gliomagenesis. 27 Since HCMV proteins and nucleotide sequences seem to be present in most GBMs 16,[28][29][30] and that HCMV-IE expression is a prognostic marker for poor patient survival irrespective of the GBM subtype, 18 our present model of HCMV infection of primary GBM cells appears to recapitulate early events during glioma development.…”

Influence of congenital human cytomegalovirus infection and the NKG2C genotype on NK‐cell subset distribution in children

“…42: 3256-3266 Immunity to infection 3257 lifelong latent state, occasionally undergoing reactivation, but may have a pathogenic role in immunodeficient and immunosuppressed patients [1][2][3]. Moreover, HCMV has been associated with atherosclerosis, lymphoproliferative disorders, and glioblastoma, as well as with an accelerated immunosenescence and a shorter lifespan [4][5][6][7]. Vertical transmission of HCMV during pregnancy is considered the most common cause of congenital infection worldwide, affecting ∼0.2-2% of infants and potentially causing fetal lesions [8][9][10].…”

The prevalence of human cytomegalovirus DNA in gliomas of Brazilian patients

“…However, more studies investigating the importance of HCMV in brain tumours have emerged. Mitchell et al (2008) detected HCMV in the tumours and peripheral blood of patients diagnosed with GBM and normal controls using IMH, ISH and PCR of viral DNA. They showed that a high percentage (> 90%) of GBM tumours were associated with HCMV nucleic acids and proteins.…”