Molecular alterations in pediatric brainstem gliomas.

Area of Science:

• Pediatric Oncology
• Neuro-oncology
• Molecular Pathology

Background:

• Diffuse intrinsic pontine gliomas (DIPGs) historically had a poor prognosis, diagnosed via clinical and imaging findings.
• Recent reclassification identifies DIPGs with H3 K27 mutations as diffuse midline gliomas, but overlap and survivor characteristics remain unclear.

Purpose of the Study:

• To investigate the molecular landscape of clinically diagnosed DIPGs.
• To determine the frequency of H3 K27 mutations in DIPGs.
• To analyze genetic alterations in long-term DIPG survivors.

Main Methods:

• Analysis of tumor samples from 23 children (including 2 long-term survivors) diagnosed with DIPG.
• Next-generation sequencing (NGS) for genetic alterations.
• Immunohistochemistry (IHC) for protein expression (H3 K27, cMYC).

Main Results:

• H3 K27 mutations were identified in 87% (20/23) of tumors, reclassifying them as diffuse midline gliomas.
• Neither long-term survivor harbored H3 K27 mutations; one had an IDH1 mutation.
• TP53 mutations were common (10/23), with other alterations including MET, PDGFRA, and SMARCA4.

Conclusions:

• The majority of DIPGs are molecularly classified as H3 K27-mutated diffuse midline gliomas.
• Long-term DIPG survivors represent a distinct molecular subgroup lacking H3 K27 mutations.
• IDH1 mutations, previously thought absent, can occur in pediatric brainstem gliomas.