Incidence of KRAS G12C mutations in genitourinary malignancies; emerging target in precision medicine

Kelly Crane1, K. R. Seetharam Bhat1,4, P. Grivas2, Andrea Necchi2, Gennady Bratslavsky1, Oleg Shapiro1, Joseph M. Jacob1, Hanan Goldberg1,4, Rebecca Sager1 and Jeffery S. Ross3 1 Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA 2 Hospital San Raffaele, Milan, Italy 3 Foundation Medicine, Boston, MA 02210, USA 4 Upstate Urology at MVHS, Utica, NY 13502, USA Correspondence to: K. R. Seetharam Bhat, email:bhatkuls@upstate.edu Keywords: KRAS mutation; genitourinary malignancy; precision medicine; emerging target Received: September 15, 2025 Accepted: July 13, 2026 Published: August 19, 2026 Copyright: © 2026 Crane et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Purpose: The discovery of KRAS G12C as a therapeutic target has transformed oncology with the development of specific inhibitors. This study aimed to characterize the prevalence and clinicogenomic features of KRAS G12C mutations in genitourinary malignancies, an area with limited prior data despite recent FDA approvals of KRAS G12C-targeted therapies. Materials and Methods: Comprehensive genomic profiling was performed on 13,654 formalin-fixed paraffin-embedded specimens, including 1,453 renal clear cell carcinomas (RCCC), 3,879 urothelial bladder carcinomas (UBC), and 8,322 prostate acinar adenocarcinomas (PAAC). Tumor mutational burden (TMB), microsatellite instability (MSI), and PD-L1 expression (Dako 22C3) were also assessed. Results: KRAS alterations were identified in 7 RCCC (<1%), 202 UBC (5.2%), and 158 PAAC (1.9%) cases. KRAS G12C variants were detected in 0 RCCC (0%), 24 UBC (12%), and 1 PAAC (<1%) cases. No KRAS G12C-mutated tumors showed MSI-high status. In UBC, KRAS G12C-positive cases demonstrated significantly lower TERT co-mutations and higher KDM6A alterations compared to KRAS G12C-negative cases (both p < 0.05). Age and sex distributions were similar across subtypes. Predominant co-alterations included VHL, SETD2, and PBRM1 in RCCC, and TP53, CDKN2A, and TERT in UBC. Conclusions: KRAS G12C mutations occur infrequently in major genitourinary malignancies. However, given the expanding therapeutic landscape of KRAS G12C inhibitors and potential for basket trials, further investigation in bladder and prostate cancers is warranted. These agents may offer meaningful benefit to the small subset of patients harboring this actionable alteration.