Abstract
AbstractDiffuse 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.
Funder
Oregon Health and Science University
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology (clinical),Pathology and Forensic Medicine
Reference28 articles.
1. Ostrom QT, Price M, Neff C, Cioffi G, Waite KA, Kruchko C et al (2022) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2015–2019. Neuro Oncol 24(Suppl 5):v1–v95
2. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D et al (2021) The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol 23(8):1231–1251
3. WHO Classification of Tumours Editorial Board (2021) World Health Organization classification of tumours of the central nervous system. 5th ed. Lyon: International Agency for Research on Cancer
4. Horbinski C, Nabors LB, Portnow J, Baehring J, Bhatia A, Bloch O et al (2023) NCCN guidelines(R) insights: central nervous system cancers, version 2.2022. J Natl Compr Cancer Netw 21(1):12–20
5. Braunstein S, Raleigh D, Bindra R, Mueller S, Haas-Kogan D (2017) Pediatric high-grade glioma: current molecular landscape and therapeutic approaches. J Neurooncol 134(3):541–549