Absence of cytomegalovirus in high‐coverage DNA sequencing of human glioblastoma multiforme

Abstract

Cytomegalovirus (CMV) has been proposed to be associated with glioblastoma multiforme, but there are conflicting results including lack of CMV mRNA in transcriptome sequencing data. Here, we utilized deep-coverage whole-genome sequencing data to detect latent CMV DNA in surgically resected tumors and to assess the relative proportions of viral and human DNA. We did not find traces of CMV in 52.6 billion DNA sequencing reads from 34 glioblastomas. By statistical analysis, we conclude that should the virus be present in these tumors, the average CMV level does not exceed one virus per 240,000 tumor cells (99% CI).Cytomegalovirus (CMV), a large double-stranded DNA virus of the Herpesviridae family, has been implicated in the development and progression of human gliomas.1 CMV-specific proteins have, in some immunohistochemical studies, been detected in >95% of resected glioblastoma multiforme tumors, and intratumoral CMV nucleic acids have been found using, for example, in situ hybridization and PCR. [2][3][4][5] It has been suggested that the oncogenic properties of CMV could be related to induction of low-grade inflammation, and CMV proteins have also been ascribed oncomodulatory properties.

1410 Absence of human cytomegalovirus infection in childhood brain tumors

“…This data denoted that HCMV did not replicate in GBM tissue and, therefore, the treatment with valganciclovir might be ineffective. They concluded that previously presented results of HCMV DNA in GBM might be attributed to low-level contamination from adjacent leukocytes [23].…”

Detection of human cytomegalovirus in glioblastoma among Taiwanese subjects

“…Since Cobbs and colleagues reported the presence of HCMV in malignant gliomas [8], the relationship between HCMV and GBM has been debated for more than a decade. Several studies reported high prevalence of HCMV in GBMs [11–19], while the others failed to identify any HCMV [20–27]. The discrepancy could be the differences in the sensitivities of the assays employed in different studies.…”

“…Colocalization of US28 and phosphorylated STAT3 (p-STAT3) in GBM and poor prognosis of p-STAT3 abundant GBM had also been reported [10]. However, the reported prevalence of HCMV in GBMs ranged from 0% to 100% [11–27]. The roles of HCMV in glioma development and progression are also controversial in recent years [28].…”

Application of “Omics” Technologies for Diagnosis and Pathogenesis of Neurological Infections

“…Having important therapeutic implications, unbiased next generation sequencing has been recently applied to glioblastoma samples to find a definitive answer. In one study, high coverage DNA sequences of 34 glioblastoma samples failed to detect CMV DNA in surgically resected tumors [16]. In another study on high-grade glioma samples, NGS detected viral sequences belonging to EBV and roseolovirus (HHV-6 and HHV-7) but not human CMV in the samples [17].…”

“…One interesting example is the controversial association between viruses and neurological malignancies, including the aggressive brain tumor, glioblastoma [15,16]. The presence of CMV genomic DNA and transcribed mRNAs has been reported in glioblastoma samples [15].…”