MOLECULAR CHARACTERIZATION OF THE SJMB12 CLINICAL TRIAL FOR CHILDREN AND YOUNG ADULTS WITH NEWLY DIAGNOSED MEDULLOBLASTOMA

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.