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. Their biological and clinical significance is unknown.
Clinical details for children <18 years with embryonal tumors, registered in the International RRD Consortium, were retrieved from their primary physicians. Cases were centrally reviewed, and high-throughput sequencing performed on the Illumina platform. Medulloblastoma subgrouping was performed using Nano-string and DNA-methylation arrays. Genomic signature profiles were extracted. Clinical variables and genomic data were analysed using the SPSS and R-statistical environments.
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 median age of 7-years (IQR: 5;11). All but one exhibited clinical cues of germline RRD (café-au-lait macule, or a significant family history), 60% had consanguinity, with synchronous/metachronous tumors reported in 40%.
Medulloblastomas with RRD exhibited anaplastic histology (50%), SHH-subgroup (78%), majority with TP53-mutation (50% among SHH, and 80% overall). Importantly, 70% harboured POLE/POLD1 mutations, resulting in median tumor mutation burden of 164 mut/mb. POL-mutated tumors were significantly ultra-hypermutated (>100 mut/mb) than tumors with MMR-deficiency alone (p=0.015). Despite having localized disease at diagnosis, the median survival for the entire cohort was 17-months (95% CI: 10 to 23). Predicted 3 year overall survival was 37% for medulloblastoma, with no survivors among other embryonal tumors.
This is the largest cohort of replication repair deficient medulloblastoma reported till date. The tumors demonstrate anaplasia, belong to SHH-subgroup, harbour somatic mutations in TP53 and/or POLE/POLD1, are hypermutated, and have very poor survival with current chemo-irradiation approaches. These biologically unique tumors, discovered through a robust international collaboration, expand the spectrum of high-risk TP53-mutant SHH-medulloblastoma and SHH-medulloblastoma with germline predisposition, and need novel strategies for treatment.