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Video

Cell signaling and signaling pathways

Session: Abstract Concurrent Session: Basic Science III

CSIG-24 - Linear grading coefficient reveals embryonic development gene signature as treatment-independent prognostic factor in IDH-mutant astrocytoma 

Saturday, November 18, 2023
8:05 AM – 8:15 AM PT
Location: Room 109-110
Non-CME

Background: Since there is variation in prognosis within grade II/III and grade IV IDH-mutant astrocytomas, we sought to identify features that may aid further tumor grading.

Methods: RNAseq was performed on IDH-mutant astrocytomas from the CATNON trial and overlaid with matching genome-wide methylation data. This dataset was extended by multi-omics data of IDH-mutant astrocytomas from the TCGA and GLASS-NL studies. We defined a linear grading coefficient (LGC) based on calibrated DNA methylation-based probability scores and performed differential gene expression (DGE) regression analysis on the LGC. Statistical analyses were intersected across the CATNON and TCGA cohorts ("discovery set") and validated on GLASS-NL. Single-nucleus RNA-sequencing (snRNAseq) data of high-grade IDH-mutant astrocytomas were utilized to explore the source of expression signals. Immunofluorescence was used to confirm findings on protein level.

Results: DGE regression analysis revealed that higher-grade IDH-mutant tumors (high LGC) exhibited mRNA upregulation of key embryonic developmental transcription factors (HOX[A/C/D], NKX, PAX, and TBX). Although the vast majority of CpG sites in LGC high tumors were hypomethylated, homeobox genes were strongly hypermethylated in our discovery set. HOX gene clusters showed gene-ordered (differential) expression where e.g. HOXD10 >D9 >D8 >D4 >D1 and HOXA3 >A7 >A9 >A13 suggesting derepression of enhancer sequences up/downstream of the gene cluster. Our expression-based embryonic development signature was positively correlated with, but not restricted to, the G-CIMP-low subtype and homozygous CDKN2AB deletion. The signature was prognostic (log-rank test) on both the discovery (CATNON: p< 0.0005, TCGA: p< 0.0005) and validation set (GLASS-NL: p< 0.005). As our signature was developed on molecular data from primary resections, its prognostic value is treatment-independent. SnRNAseq on high-grade IDH-mutant astrocytomas indicated expression of embryonic development genes from tumor cells, not restricted to the stemness program.

Conclusion: Our study highlights upregulation of embryonic development genes as potential molecular mechanism associated with malignancy of IDH-mutant astrocytomas.