CTP-19. Molecular characterization of the SJMB12 clinical trial for children and young adults with newly diagnosed medulloblastoma
Bibliographic record
Abstract
Abstract The SJMB12 (NCT01878617) clinical trial introduced a molecular subgroup-based approach to the treatment of newly diagnosed medulloblastoma by stratifying 649 evaluable patients into WNT, SHH, and non-WNT/non-SHH strata. While the genomic landscape of medulloblastoma has been extensively characterized, most prior studies analyzed heterogenous or non-trial-associated cohorts, which may not capture the true distribution of oncogenic drivers within a clinically homogeneous population. To address this limitation, we used 1) Illumina EPIC DNA methylation array for subgroup/subtype classification and detection of copy number alterations; 2) whole exome sequencing for detection of single-/multi-nucleotide variants and small insertions/deletions; 3) RNA sequencing for detection of gene overexpression and fusions. In the WNT-stratum (n=90), 96% of profiled tumors harbored canonical exon 3 hotspot mutations in CTNNB1, while the remaining 4% exhibited inactivation of APC, consistent with aberrant WNT/β-catenin pathway activation. Additionally, we identified mutually exclusive loss-of-function mutations affecting several genes on chromosome 6 - LATS1 (8%), FOXO3 (8%), and CSNK2B (9%), co-occurring exclusively with monosomy 6. In the SHH-stratum (n=107), 51% of tumors exhibited PTCH1 inactivation, which was the most prevalent gene-level alteration. Germline loss-of-function variants in ELP1 or TP53 were observed in ~30% of cases, highlighting the clinical utility of germline testing. Three patients exhibited hypermutator phenotypes, with tumor mutational burdens 100x higher than the cohort median. These individuals carried pathogenic germline variants in mismatch repair genes MSH6 or PMS2, consistent with Lynch/Turcot type I syndromes. Notably, two of the three patients also harbored somatic POLE mutations, likely contributing to replication error–driven mutagenesis. In the nonWNT/nonSHH stratum (n=452), beyond known drivers, we identified a novel mechanism of GFI1B enhancer hijacking resulting from an interchromosomal translocation, as opposed to proximal structural variants. The molecular results presented here will be further integrated with survival outcomes and used to inform the design of future clinical trials.
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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 | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".