{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T07:23:43Z","timestamp":1787901823866,"version":"build-2784847793"},"reference-count":28,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T00:00:00Z","timestamp":1701820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Recent data suggests that HER2-targeted treatment is efficacious in urothelial carcinoma (UC). We investigated the genomic, transcriptomic, and immune landscapes and clinical outcomes in UC segmented by ERBB2 expression. Methods: NextGen DNA\/RNA sequencing was performed for 4743 UC tumors. A total of 3% (124\/4125) of tumors had HER2 IHC and whole transcriptome sequencing (WTS) data. ERRB2-high and -low tumors were defined by \u226575th and &lt;25th percentiles of ERBB2 expression, respectively. PD-L1 (SP142) positive staining was defined as \u22652+ and \u22655%. HER2 (4B5) positive staining was defined as \u22653+ and &gt;10% or 2+ and &gt;10% with positive HER2 in situ hybridization (ISH). Results: Of the patients who were ERBB2-high, 79% (61\/77) were HER2 positive via IHC. Tumors from lower tract UC had higher ERBB2 expression compared to upper tract UC (50 v 40 median TPM (mTPM), p &lt; 0.001). ERBB2 expression was similar between primary and metastatic tumors (47 v 47 mTPM, p = 0.95). ERBB2-high tumors had a higher prevalence of pathogenic mutations in pTERT, ERBB2, and ELF3 versus ERBB2-low tumors, p &lt; 0.001. ERBB2-high tumors had higher expressions of ADC target genes NECTIN4 (12 v 8 mTPM) and TACSTD2 (366 v 74 mTPM) versus ERBB2-low (p &lt; 0.001), as well as better overall survival from time of tissue sampling than ERBB2-low (HR 1.71, p &lt; 0.001). Conclusion: Our study demonstrated a high concordance between HER2 expression by IHC and ERBB2 gene expression by WTS in UC. Differences in ADC target expression between ERBB2-high vs. ERBB2-low UC may provide a rationale for combination treatment strategies with HER2-ADC. The association between high ERBB2 expression and survival advantage warrants further investigation.<\/jats:p>","DOI":"10.3390\/cancers15245721","type":"journal-article","created":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T03:48:41Z","timestamp":1701834521000},"page":"5721","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The Genomic Landscape of Urothelial Carcinoma with High and Low ERBB2 Expression"],"prefix":"10.3390","volume":"15","author":[{"given":"Agreen","family":"Hadadi","sequence":"first","affiliation":[{"name":"Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harris B.","family":"Krause","sequence":"additional","affiliation":[{"name":"CARIS Life Sciences, Inc., Irving, TX 75039, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8494-8031","authenticated-orcid":false,"given":"Andrew","family":"Elliott","sequence":"additional","affiliation":[{"name":"CARIS Life Sciences, Inc., Irving, TX 75039, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline T.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bassel","family":"Nazha","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara R.","family":"Harik","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley C.","family":"Carthon","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5681-3110","authenticated-orcid":false,"given":"Benjamin","family":"Miron","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chadi","family":"Nabhan","sequence":"additional","affiliation":[{"name":"CARIS Life Sciences, Inc., Irving, TX 75039, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro C.","family":"Barata","sequence":"additional","affiliation":[{"name":"Section of Hematology and Medical Oncology, Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA"},{"name":"University Hospital Seidman Cancer Center, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Saleh","sequence":"additional","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanquan","family":"Yang","sequence":"additional","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana R.","family":"McKay","sequence":"additional","affiliation":[{"name":"University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehmet A.","family":"Bilen","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,6]]},"reference":[{"key":"ref_1","unstructured":"American Cancer Society (2023). 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