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Tumor mutational burden ( TMB ) and mutational signatures reflect the process of mutation accumulation in cancer. However, the significance of these emerging characteristics remains unclear. In the present study, we used whole‐exome sequencing to analyze the  TMB  and mutational signature in solid tumors of 4046 Japanese patients. Eight predominant signatures—microsatellite instability, smoking,  POLE ,  APOBEC ,  UV , mismatch repair, double‐strand break repair, and Signature 16—were observed in tumors with  TMB  higher than 1.0 mutation/Mb, whereas  POLE  and  UV  signatures only showed moderate correlation with  TMB , suggesting the extensive accumulation of mutations due to defective  POLE  and  UV  exposure. The contribution ratio of Signature 16, which is associated with hepatocellular carcinoma in drinkers, was increased in hypopharynx cancer. Tumors with predominant microsatellite instability signature were potential candidates for treatment with immune checkpoint inhibitors such as pembrolizumab and were found in 2.8% of cases. Furthermore, based on microarray analysis, tumors with predominant signatures were classified into 2 subgroups depending on the expression of immune‐related genes reflecting differences in the immune context of the tumor microenvironment. Tumor subpopulations differing in the content of infiltrating immune cells might respond differently to immunotherapeutics. An understanding of cancer characteristics based on  TMB  and mutational signatures could provide new insights into mutation‐driven tumorigenesis.

Mutational burden and signatures in 4000 Japanese cancers provide insights into tumorigenesis and response to therapy