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Gene Expression Changes Associated with Developing Resistance to Diffuse Intrinsic Pontine Glioma Treatments
Laura K. Harris
Pages - 40 - 57     |    Revised - 30-11-2021     |    Published - 31-12-2021
Volume - 14   Issue - 3    |    Publication Date - December 2021  Table of Contents
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KEYWORDS
Panobinostat, DIPG, GSEA, Meta-analysis, Gene Expression.
ABSTRACT
Background: Diffuse Intrinsic Pontine Glioma (DIPG) is a highly lethal pediatric brainstem tumor with limited treatment options. This work is the first to analyze differential gene expression across DIPG treatments to use a Gene Set Enrichment Analysis (GSEA)-based meta-analysis approach in identifying expression changes potentially contributing to the development of therapeutic resistance.

Methods: This work defines 14 gene signatures representing six individual and panobinostat combination treatments of DIPG patient-derived cell cultures. GSEA is used to define positive and negative panobinostat gene panels from GSEA-identified leading-edge genes using two panobinostat signatures. GSEA then is used to verify enrichment and leading-edge gene membership of panobinostat panels in two independent panobinostat signatures. Analysis is then extended to five individual and five panobinostat combination signatures. Genes most associated with treatment resistance are predicted by intersecting membership of GSEA-identified leadingedges across signatures.

Results: Significant enrichment is observed between panobinostat treatment identification signatures, from which the positive (25 genes) and negative (35 genes) panobinostat panels are defined. Non-random significant enrichment is observed between panobinostat panels and verification signatures, from which 17 over- and 30 under-expressed genes are shared across leading-edges. Considering other DIPG treatments individually and in combination with panobinostat, significant non-random enrichment is observed across treatment signatures, except 5-azacytidine, for the negative panobinostat panel. Six negative panobinostat panel genes, PHF19, ASCL1, KCNK2, EBP, ITPRIPL1, and LIN9, are found across treatment signature leading-edges regardless of treatment mechanism of action or combination with panobinostat.

Conclusion: This meta-analysis identifies gene expression changes associated with DIPG. treatment. These changes may contribute to developing therapeutic resistance.
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Dr. Laura K. Harris
Institute for Cyber Enabled Research, Michigan State University, East Lansing, 48824 - United States of America
oesterei@msu.edu


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