# High human cytomegalovirus antigen expression in pediatric medulloblastoma tissue is associated with poor event-free survival

## TL;DR

High levels of a virus called HCMV in pediatric brain tumor tissue are linked to worse survival outcomes in children with medulloblastoma.

## Contribution

This is the first study to show that high HCMV late antigen expression is an independent predictor of poor survival in pediatric medulloblastoma.

## Key findings

- High HCMV-LA expression was an independent predictor of poor event-free survival (HR = 4.334, p = .027).
- The HCMV gene UL88 was most abundantly expressed in medulloblastoma samples, especially in Group 3 tumors.

## Abstract

Despite advancements in treatment, 5-year survival for medulloblastoma (MB) remains 60%-70%. Human cytomegalovirus (HCMV) has been implicated as an oncomodulator in MB, but its impact on survival has not been explored. This study evaluates HCMV expression in pediatric MB tissue and its association with molecular risk groups and survival.

A retrospective study of pediatric MB cases (≤19 years) from 2007 to 2023 was conducted using the WHO 2021 classification, the Northcott brain-tumor classifier, and the SIOP-Europe/ERN PaedCan risk stratification. HCMV immediate-early (HCMV-IE) and late-antigen (HCMV-LA) expression were assessed by optimized immunohistochemistry, and whole-genome sequencing (WGS) data from 20 tumors were analyzed for viral gene expression.

Forty-five patients (mean age 8.2 years; 22% ≤3 years) were included: WNT (18%), SHH TP53-wildtype (18%), and non-WNT/non-SHH (64%). Twenty percent of MB belonged to low-risk, 33% to standard-risk, and 47% to high-risk (HR-MB) groups. Four tumors exhibited MYC/N amplification. HCMV-LA positivity was found in 84% of cases, with 53% showing high expression (≥25% of cells). Cox-regression identified HR-MB (HR = 4.197, p = .021) and high HCMV-LA (HR = 4.334, p = .027) as independent predictors of poor outcomes. WGS revealed UL88 as the most abundantly expressed HCMV gene (log2[TPM+1] ≈ 14-15), with maximal expression in Group 3 MB.

This study provides the first evidence linking high HCMV-LA expression to adverse outcomes and high-risk molecular features in pediatric MB. UL88 emerged as the most strongly expressed HCMV gene across MB samples. These findings suggest a potential prognostic and therapeutic role for HCMV in MB, warranting validation in larger, prospective cohorts.