IDH-mutant gliomas with additional class-defining molecular events

Area of Science:

• Neuro-oncology
• Molecular Pathology
• Genomics

Background:

• The 2016 WHO classification stratifies IDH-mutant gliomas based on co-occurring genetic events.
• Existing research explores stratifying IDH-mutant gliomas by prognostically significant molecular events.
• Systematic description of co-occurring class-defining driver alterations in IDH-mutant gliomas is lacking.

Purpose of the Study:

• To systematically identify and describe IDH-mutant gliomas with co-occurring class-defining driver alterations.
• To investigate the clinical, histological, and genetic profiles of these rare gliomas.
• To explore the potential therapeutic and prognostic implications of these co-occurring alterations.

Main Methods:

• Searched institutional sequencing databases, The Cancer Genome Atlas (TCGA), and cBioPortal for IDH-mutant gliomas with specific alterations.
• Reviewed clinical information, histology, and genetic profiles for identified cases.
• Collaborated with an outside institution to identify additional cases with NTRK fusions.

Main Results:

• Identified 18 IDH-mutant gliomas with co-occurring pathogenic alterations in FGFR, BRAF, or NTRK.
• These dual-mutated gliomas were hemispheric, with a mean age at diagnosis of 36.2 years.
• Notable co-occurring events included MYCN, RB, and PTEN alterations; one patient with IDH1/FGFR1 mutation survived 20 years.

Conclusions:

• IDH-mutant gliomas with co-occurring FGFR, NTRK, or BRAF alterations are rare but may have significant prognostic and therapeutic implications.
• These findings suggest that single-gene testing for IDH1 may be insufficient for comprehensive molecular profiling.
• Further exploration is needed to understand the significance of these alterations and their impact on clinical trial design for IDH-mutant gliomas.