DNA Methylation Subgroup and CNV Predict Response to Radiotherapy
Bibliographic record
Abstract
Background: Chordomas are rare aggressive primary bone cancers affecting the skull-base and spine. Standard of care treatment includes radical surgical resection and radiotherapy. Despite this, the overall survival at 10 years is only 40%, with most patients experiencing disease recurrence. Radiotherapy is a cornerstone in the treatment of chordomas, however the impact of radiotherapy remains incompletely described: not all patients appear to benefit, and many studies fail to replicate the finding of improvement in overall survival. Herein, we utilized our previously described DNA Methylation subgroups to examine sensitivity to radiation. Methods: We utilized a well annotated dataset of 68 patients from a multi-institutional 20-year series who had undergone whole genome DNA methylation profiling on the Illumina EPIC array. Copy number variance (CNVs) were extracted from the raw methylation data after normalization, with median intensity values calculated and converted to amplification and deletions defined as a log2 copy number ratio of over .3. Multivariable cox analysis and Kaplan Meyer analysis were then completed. Results: Within our cohort we found that patients with a cellular molecular subtype who had received radiation had a significantly improved overall survival on cox multivariate analysis (median survival 17.3 years, p = 0.0208) when compared to patients with a immune-infiltrative (median survival 6.0 years). The favorable nature of the cellular molecular subtype appeared to diminish if radiation was not given (median survival 1 year). This improvement in survival did not appear to be fully explained by simply delayed progression, as progression-free survival between irradiated immune-infiltrative and cellular subtypes did not differ significantly (p = 0.65). A panel of 30 target genes were investigated through CNV analysis for association with this phenomenon, for which 3 were identified: FGFR-1 heterozygous deletion ( p = 1.74e-6), GLI2 heterozygous deletion ( p = 0.0103) and KRAS homozygous amplification ( p = 0.0134). Conclusion: Overall, molecular subtype predicted through DNA methylation influenced the response to radiotherapy: patients with a cellular subtype have improved survival overall, which appears to be partially mediated through response to and enhanced response to radiotherapy which does not appear to be shared with their immune-infiltrative counterparts. Moreover, three target genes have been identified as potential targets that may be exploited to improve potentiate radiosensitivity in chordoma. Publication History Article published online: 05 February 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany
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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 | 0.002 |
| 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) | 0.002 | 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".