Urothelial Carcinoma With a Novel MET Exon 14 Skipping Alteration

Background/Aim: Urothelial cancer (UC) is the most common malignancy of the urinary tract, and outcomes in advanced disease remain poor. Comprehensive genomic profiling has revealed rare but potentially actionable alterations, including mesenchymal-epithelial transition factor (MET) exon 14 skipping events, which are well established in non-small cell lung cancer but rarely described in UC. We hereby report a case of high-grade plasmacytoid UC harboring a novel MET exon 14 skipping alteration and discuss its potential clinical relevance. Case Report: A 78-year-old man presented with pelvic pain and hematuria. Imaging showed irregular thickening of the bladder wall with bilateral ureterovesical junction and distal ureter involvement and rectal invasion, consistent with unresectable stage IVA (cT4N0) plasmacytoid UC. He received carboplatin-gemcitabine followed by maintenance avelumab. Next-generation sequencing of tumor tissue identified a novel intronic MET splice-site alteration, NM_000245.4: c.2942-22_2942-19delCTTT, at high variant allele frequency, predicted to cause exon 14 skipping; this result was confirmed on an independent panel, and no additional driver variants were detected. Conclusion: This case broadens the spectrum of MET exon 14 skipping events in UC by documenting a novel intronic c.2942-22_2942-19delCTTT alteration in plasmacytoid carcinoma. It underscores the importance of routine genomic profiling in advanced and histologically rare UC to uncover targetable alterations and supports consideration of MET-directed therapies or enrollment in tumor-agnostic trials for selected patients, while highlighting the need for further functional and clinical validation.