Unique Genetic and Epigenetic Alterations in Glioblastoma Long‐Term Survivors: Insights From Two Clinical Cases

TL;DR

This paper explores the genetic and epigenetic features of two glioblastoma patients with unusually long survival, revealing unique molecular profiles.

Contribution

The study identifies novel genetic alterations and molecular subtypes in long-term glioblastoma survivors.

Findings

AR10-046 showed MSH6 mutations, high tumour mutational burden, and atypical chromosomal changes.

AR10-037 exhibited MDM2 amplification and chromothripsis with new gene fusions.

These cases highlight molecular variability in long-term glioblastoma survivors.

Abstract

The biological mechanisms driving the long survival in glioblastoma (GBM). Five‐year long‐term survival (LTS) and 10‐year survival very long‐term survival (VLTS) remain significantly understudied. Here we molecularly detailed two cases. AR10‐046 (VLTS) was affected by a giant cell‐GBM, classified as the pedHGG_RTK1a subtype according to the v12.5 Heidelberg brain tumor methylation classifier. Somatic and germline MSH6 mutations, typically in Lynch syndrome, and high tumour mutational burden were detected. The copy number variation plots showed chromosome 1q gain and chromosome 13 loss with no other typical GBM alterations. AR10‐037 (LTS) suffered from a classical GBM, identified as pedHGG_MYCN subclass. Apart from the canonical chromosome 7 gain and chromosome 10q loss, we observed MDM2 gene amplification and possible rearrangements on chromosome 12 and 18 with the typical aspect of chromothripsis, harbouring two putative new gene fusions: CPSF6::CPM and PTPRR::RAB3IP. We described two patients with peculiar tumour molecular profile, widening the scenario of clinical and molecular variability in such patients.

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