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Using AI-Based Evolutionary Algorithms to Elucidate Adult Brain Tumor (Glioma) Etiology Associated with IDH1 for
Caitríona E McInerney1, Joanna A Lynn1, Alan R Gilmore1
1Patrick G. Johnson Centre for Cancer Research, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7AE, Northern Ireland, UK.
Abstract:
Adult brain tumors (glioma) represent a cancer of unmet need where standard-of-care is non-curative; thus, new therapies are urgently needed. It is unclear whether isocitrate dehydrogenases (IDH1/2) when not mutated have any role in gliomagenesis or tumor growth. Nevertheless, IDH1 is overexpressed in glioblastoma (GBM), which could impact upon cellular metabolism and epigenetic reprogramming. This study characterizes IDH1 expression and associated genes and pathways. A novel biomarker discovery pipeline using artificial intelligence (evolutionary algorithms) was employed to analyze IDH-wildtype adult gliomas from the TCGA LGG-GBM cohort. Ninety genes whose expression correlated with IDH1 expression were identified from: (1) All gliomas, (2) primary GBM, and (3) recurrent GBM tumors. Genes were overrepresented in ubiquitin-mediated proteolysis, focal adhesion, mTOR signaling, and pyruvate metabolism pathways. Other non-enriched pathways included O-glycan biosynthesis, notch signaling, and signaling regulating stem cell pluripotency (PCGF3). Potential prognostic (TSPYL2, JAKMIP1, CIT, TMTC1) and two diagnostic (MINK1, PLEKHM3) biomarkers were downregulated in GBM. Their gene expression and methylation were negatively and positively correlated with IDH1 expression, respectively. Two diagnostic biomarkers (BZW1, RCF2) showed the opposite trend. Prognostic genes were not impacted by high frequencies of molecular alterations and only one (TMTC1) could be validated in another cohort. Genes with mechanistic links to IDH1 were involved in brain neuronal development, cell proliferation, cytokinesis, and O-mannosylation as well as tumor suppression and anaplerosis. Results highlight metabolic vulnerabilities and therapeutic targets for use in future clinical trials.
Insights
This study investigated isocitrate dehydrogenases (IDH1) in adult brain tumors, identifying potential biomarkers and therapeutic targets. Overexpressed IDH1 in glioblastoma suggests new treatment strategies may be possible.
Area of Science:
- Neuro-oncology
- Cancer Genomics
- Metabolic Pathways
Background:
- Adult brain tumors (gliomas) are largely incurable, necessitating novel therapeutic strategies.
- The role of isocitrate dehydrogenases (IDH1/2) in gliomagenesis, particularly when not mutated, remains unclear.
- Isocitrate dehydrogenase 1 (IDH1) is overexpressed in glioblastoma (GBM), potentially influencing cellular metabolism and epigenetic reprogramming.
Purpose of the Study:
- To characterize IDH1 expression and identify associated genes and pathways in adult gliomas.
- To discover novel diagnostic and prognostic biomarkers for IDH-wildtype gliomas using artificial intelligence.
- To explore potential therapeutic targets and metabolic vulnerabilities linked to IDH1 expression.
Main Methods:
- Analysis of IDH-wildtype adult gliomas from The Cancer Genome Atlas (TCGA) LGG-GBM cohort.
- Utilized a novel biomarker discovery pipeline employing artificial intelligence (evolutionary algorithms).
- Identified 90 genes correlated with IDH1 expression across different glioma subtypes and analyzed their pathway enrichment and clinical relevance.
Main Results:
- Ninety genes correlated with IDH1 expression were identified, enriched in pathways like ubiquitin-mediated proteolysis, focal adhesion, mTOR signaling, and pyruvate metabolism.
- Identified potential prognostic biomarkers (TSPYL2, JAKMIP1, CIT, TMTC1) and diagnostic biomarkers (MINK1, PLEKHM3) that were downregulated in GBM.
- Found negative correlation between prognostic gene expression and IDH1 expression, and positive correlation with methylation; two diagnostic biomarkers (BZW1, RCF2) showed inverse correlation. Only TMTC1 was validated in another cohort.
Conclusions:
- IDH1 expression is linked to specific metabolic and signaling pathways in gliomas, offering insights into tumor biology.
- Identified potential diagnostic and prognostic biomarkers, though further validation is needed.
- The study highlights metabolic vulnerabilities and suggests IDH1-associated genes as potential therapeutic targets for future clinical trials in adult brain tumors.
