TMOD-01: BCOR IS A NOVEL TUMOR SUPPRESSOR GENE IN SHH-DRIVEN MEDULLOBLASTOMA

Sonic hedgehog (SHH) medulloblastoma is the most well characterized molecular subgroup of this malignant embryonal brain tumor, accounting for 1/3rd of all medulloblastoma diagnoses. Germline/somatic alterations affecting genes in the SHH pathway occur in most cases, resulting in constitutively aberrant activation of the SHH signaling cascade. Pharmacological inhibitors of SHH signaling have shown encouraging albeit transient efficacy in treating patients with SHH subgroup disease, with most patients developing resistance to conventional inhibitors. Therefore, understanding the genetic events cooperating with aberrant SHH pathway activation in medulloblastoma is of paramount importance for the development of rational, more effective combination therapies that improve cure rates for this patient subgroup. Next-generation sequencing studies have identified the BCL6 corepressor, BCOR, as among the most frequently mutated genes in SHH subgroup patients, with the majority of observed variants inferred to result in BCOR loss-of-function. Somatic mutations and homozygous deletions of BCOR are restricted to SHH subgroup patients, suggesting that deregulation of this gene plays a critical role in potentiating SHH subgroup malignancy. To validate BCOR as a novel tumor suppressor in SHH medulloblastoma, we generated Ptch1 + /−; Atoh1-Cre; Bcorfl/fl/Bcorfl/y mice to specifically inactivate Bcor in cerebellar granule neuron progenitors in vivo, presumed cells-of-origin for this medulloblastoma subgroup. Excitingly, Ptch1 + /−; Atoh1-Cre; Bcorfl/fl/Bcorfl/y mice rapidly develop ∼100% penetrant (n = 16/16) medulloblastomas (median latency = 74 days), compared to ∼36% of mice (n = 4/11) that develop medulloblastoma (average latency = 224 days) due to loss of Ptch1 + /− alone. Histologically, tumors resulting from the Bcor null genotype are highly similar to prototypical Ptch1 + /− medulloblastomas, despite exhibiting considerable gene expression differences as determined by Affymetrix expression profiling. Studies aimed at elucidating the molecular mechanism(s) associated with the development of Bcor-deficient SHH medulloblastoma are ongoing and will be essential for extrapolation of these findings into improved treatment options for SHH medulloblastoma patients in the future.