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

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Abstract
Background: Urothelial cancer typically affects older adults, yet early-onset urothelial cancer (age 45 years and younger) cases are rising and remain poorly characterized. We hypothesized that early-onset urothelial cancer exhibits distinct clinical and genomic features that reflect a different biological etiology from standard-onset urothelial cancer. Methods: We compared clinical, pathologic, and genomic characteristics of patients with early-onset urothelial cancer vs standard-onset urothelial cancer evaluated at Memorial Sloan Kettering Cancer Center from 2000 through 2024. Clinical data included 9221 patients, with tumor and germline genomic profiling by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay in 2753 patients. Results: Early-onset urothelial cancer accounted for 335 of 9221 (3.6%) patients. Early-onset urothelial cancer patients were more likely never-smokers (43% vs 26%, P < .001), female (30% vs 25%, P = .034), and of Asian race (7.4% vs 3.1%, P < .001). Early-onset urothelial cancer tumors were more often low-grade (41% vs 23%, P < .001) and of pure nonurothelial histology (4.0% vs 1.7%, P = .003). Early-onset urothelial cancer 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 early-onset vs 17.2% of standard-onset urothelial cancer patients (P = .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: Early-onset urothelial cancer 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 early-onset urothelial cancer and supporting age- and biology-informed approaches to risk assessment, genetic counseling, and targeted therapy development.
Funding Information
  • Mark Foundation For Cancer Research
  • National Institutes of Health
  • National Institutes of Health
  • National Cancer Institute
  • MSK SPORE in Bladder Cancer (P50 CA221745)
  • MSK Cancer Center Support Grant (P30 CA008748)
  • American Society of Clinical Oncology Young
  • National Institutes of Health
  • Ruth L. Kirschstein National Research Service (T32 CA082088)
  • Bochner Fleischer Scholarship and an NCI Mentored Clinical Scientist Research Career Development (K08 CA272960)

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