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In the present study, we used whole\u2010exome sequencing to analyze the <jats:styled-content style=\"fixed-case\">TMB<\/jats:styled-content> and mutational signature in solid tumors of 4046 Japanese patients. Eight predominant signatures\u2014microsatellite instability, smoking, <jats:styled-content style=\"fixed-case\">POLE<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> APOBEC<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> UV<\/jats:styled-content>, mismatch repair, double\u2010strand break repair, and Signature 16\u2014were observed in tumors with <jats:styled-content style=\"fixed-case\">TMB<\/jats:styled-content> higher than 1.0 mutation\/Mb, whereas <jats:styled-content style=\"fixed-case\">POLE<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">UV<\/jats:styled-content> signatures only showed moderate correlation with <jats:styled-content style=\"fixed-case\">TMB<\/jats:styled-content>, suggesting the extensive accumulation of mutations due to defective <jats:styled-content style=\"fixed-case\">POLE<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">UV<\/jats:styled-content> 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\u2010related 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 <jats:styled-content style=\"fixed-case\">TMB<\/jats:styled-content> and mutational signatures could provide new insights into mutation\u2010driven tumorigenesis.<\/jats:p>","DOI":"10.1111\/cas.14087","type":"journal-article","created":{"date-parts":[[2019,6,1]],"date-time":"2019-06-01T17:07:45Z","timestamp":1559408865000},"page":"2620-2628","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Mutational burden and signatures in 4000 Japanese cancers provide insights into tumorigenesis and response to therapy"],"prefix":"10.1111","volume":"110","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6000-5899","authenticated-orcid":false,"given":"Keiichi","family":"Hatakeyama","sequence":"first","affiliation":[{"name":"Medical Genetics Division Shizuoka Cancer Center Research Institute Nagaizumi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Nagashima","sequence":"additional","affiliation":[{"name":"Cancer Diagnostics Research Division Shizuoka Cancer Center Research Institute Nagaizumi Japan"},{"name":"Corporate Project Office SRL Inc. 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