Comprehensive clinical and genomic analysis of early onset cancer of the bladder and upper urinary tract.

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.