"KRAS G12C mutations occur infrequently in major genitourinary malignancies."
BUFFALO, NY – August 28, 2026 – A new research paper was published in Volume 17 of Oncotarget on August 19, 2026, titled " Incidence of KRAS G12C mutations in genitourinary malignancies; emerging target in precision medicine ."
The study was led by first author Kelly Crane from the Department of Urology at SUNY Upstate Medical University . The corresponding author is K. R. Seetharam Bhat, who is affiliated with the Department of Urology at SUNY Upstate Medical University and Upstate Urology at MVHS .
KRAS is one of the most extensively studied oncogenes in cancer, and the G12C variant has become clinically important following the development of mutation-specific inhibitors. Although KRAS G12C-targeted therapy is established in other malignancies, its frequency and genomic characteristics in genitourinary cancers have remained less well defined.
To address this gap, the researchers performed comprehensive genomic profiling of 13,654 tumor specimens from patients with metastatic disease, including 1,453 renal clear cell carcinomas, 3,879 urothelial bladder carcinomas, and 8,322 prostate acinar adenocarcinomas. Tumor mutational burden, microsatellite instability, and PD-L1 expression were also evaluated.
Across the full cohort, KRAS alterations were detected in 367 tumors, or 2.7%, while KRAS G12C was identified in only 25 tumors, representing approximately 0.2% of all specimens. No G12C variants were found among the renal clear cell carcinomas. In urothelial bladder carcinoma, 24 of 202 KRAS-altered tumors, or 12%, carried G12C, while only one of 158 KRAS-altered prostate tumors contained the variant.
The urothelial bladder cancer findings were particularly informative. KRAS G12C-positive tumors showed significantly fewer TERT co-alterations and significantly more KDM6A alterations than KRAS G12C-negative tumors. Other frequent concurrent changes included TP53, CDKN2A, and CDKN2B. The single G12C-positive prostate tumor also carried STK11 and APC alterations.
None of the KRAS G12C-positive tumors showed microsatellite instability-high status. Median tumor mutational burden was somewhat higher in G12C-positive bladder tumors, while the single G12C-positive prostate case also showed higher TMB than the other KRAS-mutated prostate specimens. However, PD-L1 data were limited. Only one of the 24 G12C-positive bladder tumors underwent PD-L1 testing, preventing firm conclusions about immune-checkpoint biomarkers in this subgroup.
The clinical relevance of identifying this rare subgroup lies in the expanding development of KRAS G12C inhibitors. Sotorasib became the first FDA-authorized agent directed against KRAS G12C, demonstrating that mutant KRAS can be pharmacologically targeted. The authors therefore suggest that molecularly selected patients with genitourinary cancers could potentially be considered for targeted strategies or basket-type clinical trials as the therapeutic landscape expands.
"While these novel therapeutic approaches may not prove beneficial for the majority of patients with these malignancies, they may become integral in managing the subset of patients harboring the KRAS G12C alteration."
The study also highlights the value of comprehensive genomic profiling in precision oncology. Because KRAS G12C occurs in only a small minority of genitourinary tumors, comprehensive genomic profiling may help identify patients who carry this potentially actionable alteration.
Important limitations remain. Only 25 KRAS G12C-positive tumors were identified across the full cohort, including a single prostate cancer case and no renal clear cell carcinomas. PD-L1 testing was also sparse, and the study evaluated genomic prevalence rather than clinical responses to KRAS G12C inhibitors. The findings therefore define the molecular landscape but do not establish treatment efficacy in bladder or prostate cancer.
Overall, the study identifies KRAS G12C as a rare but potentially meaningful precision-medicine target in genitourinary oncology, particularly in urothelial bladder carcinoma. As KRAS G12C-directed therapies continue to expand, further clinical research will be needed to determine whether selected patients with bladder or prostate cancer can benefit from these targeted approaches.
DOI: https://doi.org/10.18632/oncotarget.28912
