(a) Violin plots show the distribution of the somatic tumor mutation burden (TMB), defined as the number of nonsynonymous coding mutations per megabase, for common principal tumor types. The width of each plot indicates the frequency of samples with a given TMB. The red line indicates the threshold for samples with a high mutation burden (13.8 mutations/Mb). (b) The distribution of observed mutation rates across all tumors sequenced was used to identify a threshold of 13.8 mutations/Mb (red line), indicative of high mutation burden. (c) Dominant mutation signatures identified in cases with a high mutation burden. The percentage of cases harboring a dominant mutation signature is shown for each principal tumor type. POLE, POLE-associated hypermutation; MMR, mismatch-repair deficiency; TMZ, temozolomide. (d) Individual tumors harboring dominant mutation signatures. Bar charts display the total number of coding mutations (gray) and the fraction of mutations explained by the major signatures (colored). Tracks below the bar charts indicate (i) POLE mutation status, (ii) MMR pathway mutation status, (iii) MSIsensor score, (iv) indel-to-SNV (single-nucleotide variant) ratio, (v) reported smoking status and (vi) cancer type. (e) Tumor type distribution for samples with a high mutation burden, dominant MMR signature and inferred MSI. (f) A 55-year-old patient with castration- and enzalutamide-resistant prostate cancer with an MMR signature (19 mutations, including 6 frameshift indels) and no clear underlying somatic or germline MMR pathway lesion. A pathogenic germline MUTYH variant was detected, which may contribute to the MSI phenotype. Upon initiation of treatment on an anti-PD-L1 immunotherapy regimen, rapid tumor regression was observed. Line charts show relative tumor size based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria and serum prostate-specific antigen (PSA) levels. MRI images show the decreasing tumor size at indicated time points. Scale bars, 10 cm.