The impact of heme biosynthesis regulation on glioma aggressiveness: Correlations with diagnostic molecular markers
Bibliographic record
Abstract
Background The prognosis of diffusely infiltrating glioma patients is dismal but varies greatly between individuals. While characterization of gliomas primarily relied on histopathological features, molecular markers increasingly gained importance and play a key role in the recently published 5 th edition of the World Health Organization (WHO) classification. Heme biosynthesis represents a crucial pathway due to its paramount importance in oxygen transport, energy production and drug metabolism. Recently, we described a “heme biosynthesis mRNA expression signature” that correlates with histopathological glioma grade and survival. The aim of the current study was to correlate this heme biosynthesis mRNA expression signature with diagnostic molecular markers and investigate its continued prognostic relevance. Materials and methods In this study, patient data were derived from the “The Cancer Genome Atlas” (TCGA) lower-grade glioma and glioblastoma cohorts. We identified diffusely infiltrating gliomas correlating molecular tumor diagnosis according to the most recent WHO classification with heme biosynthesis mRNA expression. The following molecular markers were analyzed: EGFR amplification, TERT promoter mutation, CDKN2A/B homozygous loss, chromosome 7 + /10- aneuploidy, MGMT methylation, IDH mutation, ATRX loss, p53 mutation and 1p19q codeletion. Subsequently, we calculated the heme biosynthesis mRNA expression signature for correlation with distinct molecular glioma markers/molecular subgroups and performed survival analyses. Results A total of 649 patients with available data on up-to-date molecular markers and heme biosynthesis mRNA expression were included. According to analysis of individual molecular markers, we found a significantly higher heme biosynthesis mRNA expression signature in gliomas with IDH wildtype ( p < 0.0005), without 1p19q codeletion ( p < 0.0005), with homozygous CDKN2A/B loss ( p < 0.0005) and with EGFR amplification ( p = 0.001 ). Furthermore, we observed that the heme biosynthesis mRNA expression signature increased with molecular subgroup aggressiveness ( p < 0.0005 ), being lowest in WHO grade 2 oligodendrogliomas and highest in WHO grade 4 glioblastomas. Finally, the heme biosynthesis mRNA expression signature was a statistically significant survival predictor after multivariate correction for all molecular markers ( p < 0.0005). Conclusion Our data demonstrate a significant correlation between heme biosynthesis regulation and diagnostic molecular markers and a prognostic relevance independent of these established markers. Consequently, heme biosynthesis expression is a promising biomarker for glioma aggressiveness and might constitute a potential target for novel therapeutic approaches.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".