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In this study, tumor mutation profiling was performed using whole\u2010genome sequencing in two patients with LELC of the renal pelvis. Novel candidate variants relevant to known disease genes were selected using rare\u2010variant burden analysis. Subsequently, a population\u2010based study was performed using the Surveillance, Epidemiology, and End Results (SEER), PubMed, MEDLINE, Embase, and Scopus databases to explore clinical features and prognostic risk factors. Immunohistochemical analysis revealed seven positive cytokeratin\u2010associated markers in tumor cells and five positive lymphocyte\u2010associated markers in and around the tumor area. Sub\u2010sequently, we identified <jats:italic>KDM6A<\/jats:italic> as the susceptibility gene and <jats:italic>LEPR<\/jats:italic> as the driver gene by Sanger sequencing in case 2 of LELC of the renal pelvis. Three mutation sites of the existing targeted drugs were screened: <jats:italic>CA9<\/jats:italic>, a therapeutic target for zonisamide; <jats:italic>ARVCF<\/jats:italic>, a therapeutic target for bupropion; and <jats:italic>PLOD3<\/jats:italic>, a therapeutic target for vitamin C. In a population\u2010based study, patients with primary LELC of the upper urinary tract had clinical outcomes similar to those of patients with primary upper urinary tract urothelial carcinoma (UUT\u2010UC) before and after propensity score matching at 1\u2009:\u20095. Focal subtype was an independent prognostic factor for the overall survival of patients with LELC of the upper urinary tract. The carcinogenesis of primary LELC may be due to different genetic variations, including single\u2010nucleotide variants, insertion and deletions, structural variations, and repeat regions, which may provide the basis for clinical diagnosis and treatment. The prognosis of LELC in the upper urinary tract is similar to that of UUT\u2010UC. We suggest that the focal subtype can serve as a prognostic factor for LELC of the upper urinary tract; however, further studies are required to confirm this.<\/jats:p>","DOI":"10.1002\/1878-0261.13307","type":"journal-article","created":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T15:23:57Z","timestamp":1661268237000},"page":"3666-3688","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Analysis of genetic profiling, pathomics signature, and prognostic features of primary lymphoepithelioma\u2010like carcinoma of the renal pelvis"],"prefix":"10.1002","volume":"16","author":[{"given":"Bo","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Urology Second Affiliated Hospital of Dalian Medical University  China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanbin","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Urology Second Affiliated 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