Abstract Background: Mutation signatures have been catalogued across most common cancers, providing insights into their underlying mutational processes and suggesting strategies for categorization and subphenotyping. However, these analyses have been limited to mostly adult cancers, likely due to the relative rarity of pediatric analogs and a corresponding lower mutation burden of these tumors. Here we attempted to compare mutation signatures across several pediatric cancers, given these constraints, with their corresponding adult versions. Data and Methods: From the ICGC data portal, we downloaded clinical and mutation data for pediatric brain (medulloblastoma, glioblastoma, neuroblastoma) and blood-based (acute lymphoblastic leukemia, acute myeloid leukemia) cancers. We also obtained data for related adult cancers, including glioblastoma and acute myeloid leukemia. For each cancer, we characterized mutation patterns using trinucleotides centered at somatic SNVs and then estimated the composition of underlying putative COSMIC mutation signatures. For cancers with low mutation rates (impeding estimates of mutation signatures), we grouped mutations from similar samples based on clinical and molecular statuses to infer mutation signatures. Results: Each of the pediatric cancer types strongly exhibited the common cancer mutation Signature 1 (spontaneous deamination of 5-methylcytosine), as might be expected since it has been described across all adult cancer types. Further, pediatric acute myeloid leukemia and glioblastoma both harbored mutation signatures seen in their adult counterparts in addition to unexpected patterns of defective DNA mismatch repair and DNA double-strand break repair. Interestingly, for pediatric glioblastoma we identified Signatures 3, 8, 15 and 16, which were previously unidentified in adult glioblastoma and have been recently implicated in pediatric medulloblastoma. Conclusion: Our findings may be influenced by the sparsity of mutations in pediatric cancers, highlighting the need for quantifying precision in measures of mutation signatures. This notwithstanding, from our initial observations, pediatric cancers appear to exhibit a more diverse set of mutation signatures than their adult counterparts. Further, pediatric cancers of different histologies, particularly those of brain cancers, may share molecular mechanisms more than currently believed. Citation Format: Francis A. San Lucas, Philip Lupo, Austin Brown, Michael Scheurer, Paul Scheet. Exploring mutation signatures in pediatric cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2085.