We also investigated associations between the TIS and COSMIC Single Base Substitution (SBS) signatures (Fig. 2d, S4b; Supplementary Data 8) and found that TIS is largely independent of mutational signatures in pediatric brain tumors, with the most notable finding being a weakly negative correlation with SBS3 (defective homologous recombination repair; Pearson correlation = −0.17, p = 1.5 × 10−5) and SBS5 (clock-like signature, Pearson correlation = −0.19, p = 8.6 × 10−7). This evidence concerns the gene CLOCK and brain neoplasm.