Abstract

Simple SummaryMedulloblastoma is a malignant primary brain tumour that commonly occurs in children but also occurs in teenagers and young adults (TYA, aged 13–24 years) frequently enough to warrant attention. While remarkable progress has been made with paediatric tumours, TYAs with medulloblastoma represents an understudied population, lacking dedicated studies. The study aims to comprehensively characterise medulloblastoma in TYAs using data obtained from genomic technologies. It highlights that TYA medulloblastoma constitutes heterogenous molecular subgroups with distinct epigenetic and transcriptomic characteristics. Additionally, the prognostic gene signature-based score stratifies TYA patients into low- and high-risk groups and associates significantly with the outcomes. These results demonstrate unique molecular characteristics of TYA medulloblastoma that may contribute to the clinical differences at presentation between TYAs and other age groups. A better understanding of the TYA-specific biology might impact the treatment of those patients in the future.Medulloblastoma (MB) is a childhood malignant brain tumour but also occurs in teenagers and young adults (TYA). Considering that MB is heterogeneous, this study aimed to define the molecular landscape of MBs in TYAs. We collated more than 2000 MB samples that included 287 TYA patients (13–24 years). We performed computational analyses consisting of genome-wide methylation and transcriptomic profiles and developed a prognostics model for the TYAs with MB. We identified that TYAs predominantly comprised of Group 4 (40%) and Sonic Hedgehog (SHH)-activated (33%) tumours, with Wingless-type (WNT, 17%) and Group 3 (10%) being less common. TYAs with SHH tumours displayed significantly more gene expression alterations, whereas no gene was detected in the Group 4 tumours. Across MB subgroups, we identified unique and shared sets of TYA-specific differentially methylated probes and DNA-binding motifs. Finally, a 22-gene signature stratified TYA patients into high- and low-risk groups, and the prognostic significance of these risk groups persisted in multivariable regression models (P = 0.001). This study is an important step toward delineating the molecular landscape of TYAs with MB. The emergence of novel genes and pathways may provide a basis for improved clinical management of TYA with MB.

Highlights

  • When we examined the Sonic Hedgehog (SHH) subgroup, we found an overlap with all three MB subgroups, but the direction of expression changes in teenagers and young adults (TYA) varied with each MB subgroup

  • When we focused on identifying possible DNA binding motifs associated with dysregulated methylation in TYAs for each MB subgroup, we found the binding motif for the transcription factor (TF) ZBTB14 in SHH, Group 3 and Group 4 subgroups, significantly enriched in areas associated with differentially methylated probes (DMPs) that showed high methylation levels in TYAs

  • Our study has delineated the molecular landscape of TYAs with medulloblastoma

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Summary

Introduction

The teenagers and young adult (TYA) cancer population encompasses patients aged. 13–24 years old at cancer diagnosis [1]. TYAs experience a distinct set of challenges when presented with a cancer diagnosis, including inequitable access to oncology services [3]. These patients are often lost in cancer care as they age out of the paediatric practice but do not seem to fit in with the older adult practice [4]. Survival gains in this patient population have improved only modestly compared with older adults and children with cancer

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