Abstract Current knowledge of cancer genomics is biased against non-coding mutations. Here, we use whole genome sequencing data from pediatric brain tumors, combined with evolutionary constraint inferred from 240 mammals to identify genes enriched in non-coding constraint mutations (NCCMs). We compare medulloblastoma (MB, malignant) to pilocytic astrocytoma (PA, benign) and find drastically different NCCM frequencies between the two. In PA, a high NCCM frequency only affects the BRAF locus, while in MB, &gt;500 genes have high levels of NCCMs. Intriguingly, many genes are associated with different age of onset, such as HOXB1 in young patients and NUAK1 in adult patients. Our analysis points to different molecular pathways in different patient groups. These novel candidate driver genes may assist patient stratification in MB and may be useful for treatment options. One-Sentence Summary Non-coding constraint mutations implicate novel candidate genes to stratify medulloblastoma by age and subgroups.

Using evolutionary constraint to define novel candidate driver genes in medulloblastoma