Prognostic Impact of Tumor Mutational Burden in Medulloblastoma

Abstract

Medulloblastoma represents the most common pediatric malignant brain tumor. While certain prognostic factors such as histology or molecular subgroup were established previously, a considerable variety exists among children within those groups with respect to prognosis, suggesting the need for further prognostic stratification. In this analysis, we included the somatic mutational burden of 190 primary medulloblastomas from four independent studies compiled in cBioPortal for Cancer Genomics. Mutation burden was determined by whole-exome or whole genome sequencing of primary samples compared to matched blood. Survival data was available for 144 patients. Mutational burden was transformed into categorical variable. Analysis was carried out using Cox-proportional hazard ratio and log-rank test using two-sided testing. The mean mutation count across all samples was 12, range 1-91. Increasing age of diagnosis was associated with increased mutational burden (p = 2.344e-06). Unfavorable histology (LCA) was also associated with increased mutational burden (p = 6.37e-05). Mutational burden of 45 or more (n = 6) was associated with worse survival (p = 0.029), with adjustment for molecular subgroup (group3, group4, WNT SHH) p = 0.096. A multivariate analysis that adjusted for mutational burden and diagnosis age showed that group4 and WNT were independently associated with improved survival (p = 0.012 and 0.038, respectively.) This analysis demonstrates that somatic mutational burden of medulloblastoma may represent a clinically meaningful marker when combined with known prognostic parameters. Pending validation, it may be used to guide future treatment decisions and clinical trials design.