Comprehensive clinical and genomic analysis of early onset cancer of the bladder and upper urinary tract
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ID: 321481
2026
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Abstract
BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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| Authors | Hong Truong, J E Eichholz, Charlie White, Irina Ostrovnaya, Walid K Chatila, Henry Walch, Rania Sheikh, Yelena Kemel, N Liso, Jonathan Rosenberg, Gopa Iyer, David H. Aggen, S A Funt, Merve Basar, Cansu Yol, Andrew T. Lenis, Peter Reisz, Alicia Latham, Zsofia Stadler, Yonina R Murciano-Goroff, Lauren Banaszak, Abbass Mg, Liu Y, K. Eugene, 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, D B Solit, Maria I. Carlo |
| Journal | JNCI Journal of the National Cancer Institute |
| Year | 2026 |
| DOI |
10.1093/jnci/djag229
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| URL | |
| Keywords | Keywords not found |
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