Abstract

While the 5-year overall survival is better in pediatric than in adult patients diagnosed with glioblastoma (GBM), outcomes in children remain very poor. Understanding the mechanisms of tumorigenesis and tumor propagation can identify therapeutic targets to improve these outcomes. Human cytomegalovirus (CMV) proteins and nucleic acids are present in the majority of adult GBM. Indeed, CMV is emerging as a potential glioma-associated target for anti-CMV agents and cellular therapeutics. Furthermore, CMV appears to contribute to GBM’s malignant phenotype, although its role in tumorigenesis is less certain. In this cohort of 25 serially diagnosed pediatric GBMs, the largest described cohort to date, we used immunohistochemical staining and in situ hybridization to show the presence of CMV antigens pp65 and IE1-72 as well as CMV nucleic acids, respectively. Our cohort indicated either CMV antigen pp65 or IE1-72 was present in approximately 67 % of pediatric GBM samples. The majority of samples stained positive for either CMV antigen showing a cytoplasmic pattern in 25-50 % of cells within the sample at a moderate intensity, while a few samples showed nuclear staining and higher grade/intensity. Of 16 samples where in situ hybridization was performed, 13 (81 %) showed specific staining using a CMV genome specific probe cocktail. ISH positive samples showed high concordance with being pp65 or IE1-72 positive. These findings, paired with the association of CMV expression with poor prognosis and overall survival, indicate the need to further investigate how these antigens are promoting tumor growth and preventing cell death. Also, the expression of these antigens in a majority of tumor tissues should be considered for immunotherapeutic targets in cases of pediatric GBM.

Highlights

  • In children, approximately 65 % of glioblastoma (GBM) arise in the cerebrum, 20 % in the thalamus and hypothalamus, and 15 % in the posterior fossa, mostly affecting the cerebellum and brainstem [1]

  • Human cytomegalovirus (CMV) proteins and nucleic acids are present in the majority of adult GBM

  • All patients were consented on a human protocol approved by Baylor College of Medicine’s internal review board (IRB)

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Summary

Introduction

Approximately 65 % of glioblastoma (GBM) arise in the cerebrum, 20 % in the thalamus and hypothalamus, and 15 % in the posterior fossa, mostly affecting the cerebellum and brainstem [1]. While GBM in both pediatric and adult patients represents the most anaplastic and highest grade of gliomas, these tumors appear to differ in their genetic and molecular underpinnings [1]. Current treatment includes tumor resection, radiotherapy, and occasionally in children, adjuvant chemotherapy. This combination is both toxic and largely ineffective [2, 3]. GBMs exhibit numerous sophisticated defense mechanisms making them resistant to conventional therapies. They are notorious for microscopically infiltrating healthy brain, making complete resection difficult.

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