GENO-10LOSS OF IDH MUTATION IN PATIENT-DERIVED BRAIN TUMOR INITIATING CELLS
Bibliographic record
Abstract
Mutation of the IDH1 gene is found in virtually every grade II–III glioma and secondary GBM. IDH mutation is currently hypothesized as the initiating event leading to gliomagenesis, by maintaining an immature proliferative state in a common precursor cell of the astrocytic and oligodendroglial lineage, through epigenetic regulation. Our group has been working for several years to establish brain tumor initiating cell (BTIC) lines from IDH mutated gliomas. We find that IDH mutant BTICs, in addition to being refractory to in vitro culture conditions, systematically lose the IDH mutant phenotype via genetic alterations of chromosome 2, which leads to the loss of either the IDH wild type or mutant allele. Furthermore, we also observed gradual loss of chromosome 2 and IDH mutation in vivo, in a serial orthotopic xenograft model of patient-derived glioma cells. Of note, disappearance, at recurrence, of a pre-existing IDH mutation has been reported in the literature. We confirm the loss of IDH mutation and show that various chromosome 2 alterations affecting the IDH1 locus arise in a subset of cells that are being selected both in vitro and in vivo, suggesting proliferation/survival advantages. Based on our observations, we propose that even though the IDH mutation is essential for tumor initiation, it may be dispensable once a durable transformed state is acquired through the acquisition of additional mutations. The loss of IDH mutation not only represents a potential mechanism of resistance to future IDH mutant-specific therapies, but also raises the intriguing possibility that such therapeutic strategies may increase the selection pressure against the IDH mutation and may eventually lead to a more aggressive phenotype. A larger study focusing on the loss of the IDH mutation in the clinic, at recurrence, will be essential to evaluate the frequency and clinical relevance of this phenomenon.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".