Significant Association of Multiple Human Cytomegalovirus Genomic Loci with Glioblastoma Multiforme Samples

Abstract

Viruses are appreciated as etiological agents of certain human tumors, but the number of different cancer types induced or exacerbated by viral infections is unknown. Glioblastoma multiforme (GBM)/astrocytoma grade IV is a malignant and lethal brain cancer of unknown origin. Over the past decade, several studies have searched for the presence of a prominent herpesvirus, human cytomegalovirus (HCMV), in GBM samples. While some have detected HCMV DNA, RNA, and proteins in GBM tissues, others have not. Therefore, any purported association of HCMV with GBM remains controversial. In most of the previous studies, only one or a select few viral targets were analyzed. Thus, it remains unclear the extent to which the entire viral genome was present when detected. Here we report the results of a survey of GBM specimens for as many as 20 different regions of the HCMV genome. Our findings indicate that multiple HCMV loci are statistically more likely to be found in GBM samples than in other brain tumors or epileptic brain specimens and that the viral genome was more often detected in frozen samples than in paraffinembedded archival tissue samples. Finally, our experimental results indicate that cellular genomes substantially outnumber viral genomes in HCMV-positive GBM specimens, likely indicating that only a minority of the cells found in such samples harbor viral DNA. These data argue for the association of HCMV with GBM, defining the virus as oncoaccessory. Furthermore, they imply that, were HCMV to enhance the growth or survival of a tumor (i.e., if it is oncomodulatory), it would likely do so through mechanisms distinct from classic tumor viruses that express transforming viral oncoproteins in the overwhelming majority of tumor cells.

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.…”

Lack of presence of the human cytomegalovirus in human glioblastoma

“…25 Recently, another study using 12 primer pairs and semi-QPCR also revealed the significantly higher incidence of CMV-DNA in a proportion of glioblastoma samples compared with non-tumor tissues. 26 One reason for this discrepancy may be because extremely small amount of DNA can be detected by traditional PCR techniques that were utilized such as nested-PCR utilized in the previous study 1 in which 35-50 cycles of amplification followed by a second round of amplification, and HCMV DNA from cells other than the tumor cells were detected. Glioblastoma is often accompanied with reactive gliosis at the edge of the tumor tissue, and microglial cells that originate from bone marrow myeloid cells, which may be persistently infected by HCMV, 27 could have important roles in the development of gliosis.…”

Discordant humoral and cellular immune responses toCytomegalovirus(CMV) in glioblastoma patients whose tumors are positive for CMV

“…With current standard therapy, median overall survival (OS) for GBM patients is less than 15 mo after diagnosis. 1,2 An active HCMV infection, as determined by HCMV protein expression, can be detected in tumor cells in 90-100% of GBM patients; [3][4][5][6][7][8] however, the infection is absent in healthy surrounding tissues, indicating a potential oncomodulatory or oncogenic role of HCMV. We found that the median OS of GBM patients correlates with the grade of HCMV infection in tumor tissue.…”