A microdeletion event at 19q13.43 in IDH-mutant astrocytomas is strongly correlated with MYC overexpression
Acta Neuropathologica Communications, vol.12, no.1, 2024 (SCI-Expanded, Scopus)
- Publication Type: Article / Article
- Volume: 12 Issue: 1
- Publication Date: 2024
- Doi Number: 10.1186/s40478-024-01811-1
- Journal Name: Acta Neuropathologica Communications
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, EMBASE, MEDLINE, Directory of Open Access Journals
- Keywords: Integrative analysis, Gliomagenesis, MYC dysregulation, Astrocytoma, 19q deletion
- Open Archive Collection: AVESIS Open Access Collection
- Dokuz Eylül University Affiliated: Yes
Abstract
MYC dysregulation is pivotal in the onset and progression of IDH-mutant gliomas, mostly driven by copy-number alterations, regulatory element alterations, or epigenetic changes. Our pilot analysis uncovered instances of relative MYC overexpression without alterations in the proximal MYC network (PMN), prompting a deeper investigation into potential novel oncogenic mechanisms. Analysing comprehensive genomics profiles of 236 “IDH-mutant 1p/19q non-co-deleted” lower-grade gliomas from The Cancer Genome Atlas, we identified somatic genomic alterations within the PMN. In tumours without PMN-alterations but with MYC-overexpression, genes correlated with MYC-overexpression were identified. Our analyses yielded that 86/236 of astrocytomas exhibited no PMN-alterations, a subset of 21/86 displaying relative MYC overexpression. Within this subset, we discovered 42 genes inversely correlated with relative MYC expression, all on 19q. Further analysis pinpointed a minimal common region at 19q13.43, encompassing 15 genes. The inverse correlations of these 15 genes with relative MYC overexpression were re-confirmed using independent scRNAseq data. Further, the micro-deleted astrocytoma subset displayed significantly higher genomic instability compared to WT cases, but lower instability compared to PMN-hit cases. This newly identified 19q micro-deletion represents a potential novel mechanism underlying MYC dysregulation in astrocytomas. Given the prominence of 19q loss in IDH-mutant gliomas, our findings bear significant implications for understanding gliomagenesis.