{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T23:03:40Z","timestamp":1789340620955,"version":"build-2803163510"},"reference-count":17,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100009851","name":"Canon Foundation for Scientific Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009851","id-type":"DOI","asserted-by":"publisher"}]},{"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\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP26ak0101263"],"award-info":[{"award-number":["JP26ak0101263"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP26ck0106906"],"award-info":[{"award-number":["JP26ck0106906"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP26gm7010010"],"award-info":[{"award-number":["JP26gm7010010"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["21H04828"],"award-info":[{"award-number":["21H04828"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["26H02447"],"award-info":[{"award-number":["26H02447"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Human epidermal growth factor receptor 2 (HER2) has emerged as a potential therapeutic target in bladder cancer (BC), particularly with the advent of next\u2010generation antibody\u2013drug conjugates (ADCs) like trastuzumab deruxtecan (T\u2010DXd). However, the complex relationship between HER2 protein expression, genetic status, and clinical outcomes remains incompletely understood. We conducted an integrated multi\u2010omics analysis of 445 BC cases (306 muscle\u2010invasive [MIBC] and 139 non\u2010muscle\u2010invasive [NMIBC]) from the OMPU\u2010NCC cohort, a uniform Japanese clinical database. The study utilized whole\u2010exome sequencing, RNA sequencing, and refined HER2 immunohistochemistry (IHC) scoring. HER2 IHC positivity (1+\/2+\/3+) was identified in 30.1% of the cohort. An additional 8.5% exhibited faint membrane staining despite being IHC 0, indicating that detectable HER2 membrane staining was present in approximately 38.5% of cases. HER2 IHC scores showed no prognostic value, whereas\n                    <jats:italic>ERBB2<\/jats:italic>\n                    amplification, detected in 7.8% of cases, was associated with poorer survival and remained an independent adverse prognostic factor in multivariable analysis (HR, 1.76; 95% CI: 1.08\u20132.87).\n                    <jats:italic>ERBB2<\/jats:italic>\n                    amplification was accompanied by frequent co\u2010amplification of genes within the 17q12 amplicon, including\n                    <jats:italic>GRB7<\/jats:italic>\n                    ,\n                    <jats:italic>MIEN1<\/jats:italic>\n                    , and\n                    <jats:italic>PGAP3<\/jats:italic>\n                    . Molecular subtyping revealed that\n                    <jats:italic>ERBB2<\/jats:italic>\n                    amplification was enriched in the Luminal Unstable (LumU) subtype. In contrast, detectable HER2 membrane staining significantly correlated with high NECTIN4 expression, indicating an overlap between tumors expressing these two ADC targets. HER2 protein expression and\n                    <jats:italic>ERBB2<\/jats:italic>\n                    amplification represent distinct features of BC. Their integrated assessment may improve molecular stratification and guide future biomarker\u2010driven studies.\n                  <\/jats:p>","DOI":"10.1111\/cas.70534","type":"journal-article","created":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T22:30:28Z","timestamp":1789338628000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Analysis of\n                    <scp>HER2<\/scp>\n                    Expression and\n                    <scp>\n                      <i>ERBB2<\/i>\n                    <\/scp>\n                    Alterations in Bladder Cancer"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9263-4929","authenticated-orcid":false,"given":"Kensuke","family":"Hirosuna","sequence":"first","affiliation":[{"name":"Department of Urology Osaka Medical and Pharmaceutical University  Osaka Japan"},{"name":"Division of Cancer RNA Research National Cancer Center Research Institute  Tokyo Japan"},{"name":"Department of Cancer Cellular Signaling, Graduate School of Medicine The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Urology Osaka Medical and Pharmaceutical University  Osaka Japan"},{"name":"Division of Cancer RNA Research National Cancer Center Research Institute  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritoshi","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Department of Urology Osaka Medical and Pharmaceutical University  Osaka Japan"},{"name":"Division of Cancer RNA Research National Cancer Center Research Institute  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Tokushige","sequence":"additional","affiliation":[{"name":"Department of Urology Osaka Medical and Pharmaceutical University  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keita","family":"Nakamori","sequence":"additional","affiliation":[{"name":"Department of Urology Osaka Medical and Pharmaceutical University  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5238-2598","authenticated-orcid":false,"given":"Tomohisa","family":"Matsunaga","sequence":"additional","affiliation":[{"name":"Department of Urology Osaka Medical and Pharmaceutical University  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Yoshikawa","sequence":"additional","affiliation":[{"name":"Department of Urology Osaka Medical and Pharmaceutical University  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Tsutsumi","sequence":"additional","affiliation":[{"name":"Department of Urology Osaka Medical and Pharmaceutical University  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoichi","family":"Maenosono","sequence":"additional","affiliation":[{"name":"Department of Urology Osaka Medical and Pharmaceutical University  Osaka Japan"},{"name":"Division of Cancer RNA Research National Cancer Center Research Institute  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1559-1889","authenticated-orcid":false,"given":"Takuya","family":"Tsujino","sequence":"additional","affiliation":[{"name":"Department of Urology Osaka Medical and Pharmaceutical University  Osaka Japan"},{"name":"Division of Cancer RNA Research National Cancer Center Research Institute  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Ajiro","sequence":"additional","affiliation":[{"name":"Division of Cancer RNA Research National Cancer Center Research Institute  Tokyo 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