{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T07:18:04Z","timestamp":1773818284446,"version":"3.50.1"},"reference-count":30,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T00:00:00Z","timestamp":1749427200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T00:00:00Z","timestamp":1749427200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Int J of Urology"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Lynch syndrome (LS) is an inherited cancer predisposition caused by germline mutations in DNA mismatch repair (MMR) genes. Upper tract urothelial carcinoma (UTUC) is the third most common cancer associated with LS. In this study, we examined MMR protein expression in UTUC using immunohistochemistry to clarify the clinicopathological characteristics and prognostic significance of LS\u2010associated UTUC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed the expression of MLH1, MSH2, MSH6, and PMS2 by immunohistochemistry in 118 cases of UTUC treated with radical nephroureterectomy. MMR deficiency was defined as tumors exhibiting less than 5% MMR protein expression. We conducted further investigations using public databases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MMR deficiency was identified in 15 (13%) of the 118 UTUC cases. These cases were associated with younger age, papillary morphology, low grade, low stage, low neutrophil\u2010to\u2010lymphocyte ratio, high levels of CD8\u2010positive tumor\u2010infiltrating lymphocytes, and favorable prognosis. Similar findings were observed through in silico analysis. Public datasets revealed that tumor mutational burden in UTUC was significantly higher in MMR\u2010mutated cases compared to MMR\u2010normal cases. A waterfall plot showed a high frequency of FGFR3 mutation in MMR\u2010mutated cases in UTUC. Bioinformatics analysis using RNA\u2010Seq datasets showed that MMR\u2010mutated UTUC was associated with enriched gene sets for MYC targets v1 and oxidative phosphorylation. Furthermore, gene expression levels of GALNT12 and FRMD3 emerged as potential predictors of MMR mutation in UTUC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings highlight the clinical value of evaluating MMR protein expression by immunohistochemistry, which could inform treatment strategies and surveillance protocols for UTUC patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/iju.70146","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T10:55:05Z","timestamp":1749466505000},"page":"1257-1269","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinicopathological Characteristics of Upper Tract Urothelial Cancer With Loss of Immunohistochemical Expression of Mismatch Repair Proteins"],"prefix":"10.1111","volume":"32","author":[{"given":"Go","family":"Kobayashi","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Pathology, Department of Molecular Biosciences Radiation Effects Research Foundation  Hiroshima Japan"},{"name":"Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsutaro","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1525-5463","authenticated-orcid":false,"given":"Yohei","family":"Sekino","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima 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