Molecular profiling of pre- and post-treatment pediatric high-grade astrocytomas reveals acquired increased tumor mutation burden in a subset of recurrences

Acta Neuropathol Commun. 2023 Sep 5;11(1):143. doi: 10.1186/s40478-023-01644-4.


Diffuse gliomas are a heterogeneous category of primary central nervous system tumors. Due to their infiltrative growth precluding complete surgical resection, most diffuse high-grade gliomas are treated with adjuvant chemotherapy and radiation. Recurrent/progressive diffuse gliomas may show genetic differences when compared to the primary tumors, giving insight into their molecular evolution and mechanisms of treatment resistance. In adult-type diffuse gliomas with or without isocitrate dehydrogenase gene mutations, tumor recurrence/progression can be associated with mutations in genes encoding DNA mismatch repair proteins, leading to a dramatic increase in tumor mutation burden. This phenomenon is closely linked to treatment with the DNA alkylating agent temozolomide, a mainstay of adult diffuse glioma chemotherapeutic management. Post-treatment mismatch repair deficiency and acquired high tumor mutation burden is relatively unexplored in pediatric patients who have recurrent high-grade gliomas. Here, we report a molecular and histological analysis of an institutional cohort of eleven pediatric patients with paired initial and recurrent high-grade astrocytoma samples with intervening temozolomide treatment. We identified three cases with evidence for increased tumor mutation burden at recurrence, including two cases of diffuse hemispheric glioma H3 G34-mutant (one previously reported). We also show that molecular analysis by next-generation DNA sequencing and DNA methylation-based profiling enabled an integrated diagnosis per 2021 World Health Organization criteria in 10 of 11 cases (91%). Our findings indicate that increased tumor mutation burden at post-treatment recurrence is relevant in pediatric-type diffuse high-grade gliomas. Diffuse hemispheric glioma H3 G34-mutant may be particularly susceptible to this phenomenon.

Keywords: DNA mismatch repair; High-grade astrocytoma; Hypermutation; Molecular profiling; Pediatric brain tumor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Astrocytoma*
  • Child
  • Glioma*
  • Humans
  • Mutation
  • Neoplasm Recurrence, Local
  • Temozolomide


  • Temozolomide