Urothelial cancer typically affects older adults, yet early-onset urothelial cancer (EO-UC, age ≤ 45 years) cases are rising and remain poorly characterized. We hypothesized that EO-UC exhibits distinct clinical and genomic features that reflect a different biological etiology from standard-onset UC (SO-UC).
We compared clinical, pathologic, and genomic characteristics of patients with EO-UC versus SO-UC evaluated at Memorial Sloan Kettering Cancer Center from 2000 through 2024. Clinical data included 9,221 patients, with tumor and germline genomic profiling by MSK-IMPACT in 2,753 patients.
EO-UC accounted for 335/9,221 (3.6%) cases. EO-UC patients were more likely never-smokers (43% vs 26%, p < 0.001), female (30% vs 25%, p = 0.034), and of Asian race (7.4% vs 3.1%, p < 0.001). EO-UC tumors were more often low-grade (41% vs 23%, p < 0.001) and of pure non-urothelial histology (4.0% vs 1.7%, p = 0.003). EO-UC showed marked enrichment for HRAS mutations, independent of histologic subtype, and HRAS-mutated tumors had reduced APOBEC-associated mutation signatures. Germline pathogenic variants were detected in 21.0% of EO-UC vs 17.2% of SO-UC patients (p = 0.43), driven mostly by mismatch repair and MUTYH gene alterations. Rare cases of somatic mosaicism in HRAS and ERCC2 were observed in patients with very early-onset disease.
EO-UC represents a biologically distinct subset characterized by HRAS-driven oncogenesis, reduced APOBEC mutagenesis, frequent germline variants, and, rarely, somatic mosaicism. These findings suggest developmental or genetic mechanisms underlying EO-UC, and supporting age- and biology-informed approaches to risk assessment, genetic counseling, and targeted therapy development.
Journal of the National Cancer Institute. 2026 Jul 16 [Epub ahead of print]
Hong Truong, Jordan Eichholz, Charlie White, Irina Ostrovnaya, Walid K Chatila, Henry Walch, Rania Sheikh, Yelena Kemel, Nicole Liso, Jonathan Rosenberg, Gopa Iyer, David H Aggen, Samuel A Funt, Merve Basar, Cansu Yol, Andrew T Lenis, Peter Reisz, Alicia Latham, Zsofia Stadler, Yonina R Murciano-Goroff, Lauren G Banaszak, Mohammad Abbass, Ying Liu, Eugene K Cha, Alvin C Goh, Robert C Smith, Timothy F Donahue, Richard S Matulewicz, Sherri Machele Donat, Harry Herr, Victor Reuter, Diana Mandelker, Nikolaus Schultz, Kenneth Offit, Bernard H Bochner, Jonathan A Coleman, Eugene Pietzak, Hikmat Al-Ahmadie, David B Solit, Maria I Carlo
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.