Abstract LB-198: Epigenomic alterations define lethal CIMP-positive ependymomas of infancy
Bibliographic record
Abstract
Abstract Ependymomas are the third most common childhood brain tumor. These tumors arise throughout the nervous system, but in children, are most common within posterior fossa (PF). Treatment consists of surgery and radiation, as chemotherapy has demonstrated little to no survival benefit. We have shown previously that PF ependymomas are divided into two clinically and molecularly distinct subtypes, termed Group A and Group B. While Group B tumors, which have a favorable outcome (5 year survival ∼95%) and are characterized by increased copy number alterations (CNAs), Group A tumours have a poor prognosis (5 year survival ∼20%) and have few somatic CNAs. To discover somatic SNVs of PF ependymomas, we performed whole genome-, and whole exome-sequencing of 47 PF ependymomas including matched germline DNA (27 PFA, and 20 PFB). In addition, we analysed DNA methylation patterns in a discovery cohort of 79 ependymomas using methyl-binding domain-2 (MBD2) protein recovery followed by hybridization to Nimblegen 385K CpG Island Promoter Plus microarrays (MBD2-chip). Unsupervised consensus clustering of CpG methylation profiles yielded in principle two distinct subtypes of posterior fossa ependymomas (Group A and B) respectively, in a pattern highly similar to that yielded by unsupervised clustering of gene expression profiles. We validated our findings in a non-overlapping cohort of 48 PF ependymomas using an orthogonal technology (Illumina Infinium450k methylation arrays). To uncover additional epigenetic alteration we performed whole genome bisulphite-sequencing in 6 tumors and H3K27me3 ChIP-seq in 11 primary PF ependymomas. Unlike some other childhood malignancies, the rate of somatic SNVs was extremely low in PF ependymomas, with an average of 5.0 somatic non-synonymous SNVs per exome across the entire cohort. While devoid of recurrent SNVs and focal copy number aberrations, poor prognosis Group A ependymomas exhibit a CpG island methylator phenotype (CIMP+). Further, transcriptional silencing driven by CpG methylation converges exclusively on targets of the polycomb repressor complex 2 (PRC2) that represses expression of differentiation genes through tri-methylation of H3K27. CIMP positive PF ependymomas (Group A) are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland. Since epigenetic modulators are already approved drugs, this therapeutic strategy could be rapidly repurposed to treat children with ependymoma. Citation Format: Hendrik Witt, Steve C. Mack, Stefan M. Pfister, Andrey Korshunov, Michael D. Taylor, Ependymoma Collaborative Consortium. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-198. doi:10.1158/1538-7445.AM2014-LB-198
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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".