Targeted NGS-Based Mutational Signature Analysis in Hypermutated Gliomas: A Case-Centered Feasibility Assessment.

Area of Science:

• Oncology
• Genomics
• Molecular Pathology

Background:

• Gliomas typically have low tumor mutational burden (TMB) and an immunosuppressive microenvironment, limiting immunotherapy effectiveness.
• High TMB in gliomas can be acquired through temozolomide (TMZ) therapy or mismatch repair deficiency (MMRd).
• Mutational signature analysis helps elucidate the mechanisms behind somatic mutations.

Purpose of the Study:

• To assess the feasibility of mutational signature refitting using a targeted next-generation sequencing (NGS) panel in hypermutated gliomas.
• To analyze mutational patterns in gliomas with acquired high TMB in a real-world clinical setting.

Main Methods:

• Retrospective review of 28 gliomas analyzed with the Oncomine Comprehensive Assay Plus NGS panel.
• Stratification based on panel-derived TMB to identify hypermutated tumors for signature analysis.
• Mutational signature refitting performed using Signature Analyzer for Targeted Sequencing (SATS).

Main Results:

• Two gliomas showed elevated TMB: one post-TMZ therapy, the other with MSH2 deficiency.
• The TMZ-treated glioma predominantly displayed COSMIC single-base substitution signature 11 (SBS11).
• The MSH2-deficient glioma showed increased SBS1 and SBS26 signatures.

Conclusions:

• Targeted-panel mutational signature refitting can provide valuable molecular context in select hypermutated gliomas.
• Observed mutational signatures correlated with TMZ exposure and mismatch repair deficiency.
• Limited mutation counts in non-hypermutated gliomas restricted reliable signature interpretation, and clinical utility requires further study.