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BACKGROUND Mutations in mismatch repair (MMR) and DNA-polymerase (POL) genes lead to DNA replication repair deficiency (RRD), resulting in a growing group of previously under-recognized childhood brain tumors. Medulloblastoma and embryonal tumors are rarely reported in RRD. Their biological and clinical significance is unknown. METHODS We analyzed the clinical and genomic data of embryonal tumors registered in the International RRD Consortium. RESULTS Twenty-six tumors were centrally reviewed to confirm medulloblastoma (n=18), embryonal-tumor, NOS (n=5), and three glioblastoma (excluded). Embryonal tumors were observed at a young age (median: 7-years, IQR: 5;11), and all but one exhibited clinical cues (café-au-lait macules/ family history) of germline RRD. Medulloblastomas with RRD exhibited high-risk features, including anaplastic histology (50%), and SHH-subgroup with TP53-mutation (50%). Importantly, 68% harbored POLE/POLD1 mutations, resulting in median tumor mutation burden of 164 mut/mb. POL-mutated tumors were significantly ultra-hypermutated (&amp;gt;100 mut/mb) than tumors with MMR-deficiency alone (p=0.015). Synchronous and metachronous tumors were observed in 40%. However 90% of the deaths were related to the diagnosis of embryonal CNS tumor. Median survival for the entire cohort was 17-months (95% CI: 10 to 23). Predicted 3-year survival was 37% for medulloblastoma, with no survivors among other embryonal tumors. CONCLUSIONS This is the largest cohort of replication repair deficient medulloblastoma reported till date. The tumors are hypermutated, harbor somatic mutations in TP53 and/or POLE/POLD1, and have very poor survival with current chemo-irradiation based approaches. These biologically unique tumors expand the spectrum of high-risk TP53-mutant SHH-medulloblastoma, and need novel strategies for treatment.

neuro-oncology

MBRS-54. POOR SURVIVAL IN REPLICATION REPAIR DEFICIENT HYPERMUTANT MEDULLOBLASTOMA AND CNS EMBRYONAL TUMORS: A REPORT FROM THE INTERNATIONAL RRD CONSORTIUM