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This study examined the impact of clinical, environmental, and genomic factors on TMB in advanced CRC using comprehensive genomic profiling (CGP). Eighty-eight patients with advanced or recurrent CRC who underwent CGP were analyzed and compared with 701 MSS CRC cases from a public dataset. Associations between TMB and clinicopathological, environmental, and genomic factors were evaluated. The number of prior chemotherapy regimens was significantly associated with higher TMB. No associations were observed between TMB and alcohol use, smoking history, or specific chemotherapeutic classes. Although variants in\n                    <jats:italic>POLE<\/jats:italic>\n                    or\n                    <jats:italic>POLD1<\/jats:italic>\n                    were detected, all were non-pathogenic and were not linked to elevated TMB. The top 3 three most frequent genes were consistent with those in the public dataset, although variant frequencies were higher in this cohort. In MSS TMB high CRC, elevated TMB may reflect cumulative treatment-related effects rather than intrinsic hypermutagenic mechanisms, highlighting the need to interpret TMB in the context of therapeutic history.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-46050-7","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T03:49:06Z","timestamp":1775447346000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Impact of chemotherapy exposure on tumor mutation burden in advanced colorectal cancer"],"prefix":"10.1038","volume":"16","author":[{"given":"Tomoya","family":"Sudo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachiko","family":"Nagasu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshimitsu","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Fujiyoshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Kawamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Shimamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junya","family":"Fukuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maako","family":"Kikuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirona","family":"Shigyo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Koushi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Shigaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naohiro","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takefumi","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Miwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironori","family":"Koga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumihiko","family":"Fujita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,6]]},"reference":[{"key":"46050_CR1","doi-asserted-by":"publisher","first-page":"1757","DOI":"10.1056\/NEJMoa0804385","volume":"359","author":"CS Karapetis","year":"2008","unstructured":"Karapetis, C. 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All other authors do not have any competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The ethics committee of Kurume University approved this study, which followed the principles laid down in the 1964 Declaration of Helsinki and its later amendments (Approval No. 445).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All informed consent was obtained from the subject and\/or guardians.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}],"article-number":"16380"}}