Abstract 1646: A glioblastoma methylation assay (GaMA) developedfrom genomic analysis of glioma spheroid cultures predicts response toradiation therapy in patients with glioblastoma
Bibliographic record
Abstract
Abstract Radiation therapy (RT) remains one of the most effective treatments for patients with GBM and has been repeatedly demonstrated to improve survival; yet response to RT is variable. We explored the relationship between methylation status and radiation response to develop a predictor of RT response using the epigenetic data of glioma sphere-forming cells (GSCs). The DNA methylomes of 42 GSCs were profiled using Illumina Infinium 450K methylation bead arrays. 15 GSCs were irradiated with 2-, 4-, and 6-Gy RT and response determined using clonogenic assays. We discovered 168 CpG probes capable of distinguishing sensitive from resistant GSCs. To validate, we analyzed 362 TCGA GBM samples, 272 that received standard 60Gy RT and 90 treated with low or no RT. Using the glioblastoma methylation assay (GaMA) signature, we classified the samples as either RT sensitive or resistant. Survival was significantly different between the predicted sensitive vs resistant patients for those treated with standard RT (median 21.0m vs 14.7m, p<0.005). GaMA did not predict a survival difference among patients receiving no/low-dose RT, suggesting a predictive, but not prognostic, role for the signature. Using the ENCODE ChIP-Seq Significance Tool, we observed that the transcription factor EZH2 was significantly associated with the radiation resistant promoters in the GaMA signature. Among the hypermethylated genes with EZH2 binding sites, the NR2F2 promoter had the greatest number of hypermethylated CpG sites correlated to RT resistance. NR2F2 has previously been identified as negatively associated with activation of the wnt/β-catenin, a pathway associated with RT resistance of mammary progenitor cells. Expression of WNT1 in TCGA GBM cohort was negatively associated with NR2F2 expression. Our GSC RT response-based methylome analysis corroborates this association and provides a rationale for the methylation signature as a predictive biomarker of radiation response. Citation Format: Qianghu Wang, Ravesanker Ezhilarasan, Eskil Eskilsson, Joy Gumin, Jie Yang, Mona Jaffari, Ming Tang, Kenneth D. Aldape, Frederick F. Lang, Roel G.W. Verhaak, Erik P. Sulman. A glioblastoma methylation assay (GaMA) developedfrom genomic analysis of glioma spheroid cultures predicts response toradiation therapy in patients with glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1646.
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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 | 0.001 | 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 | 0.000 |
| 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".