Introduction:

KRAS, a key regulator of cellular growth and survival, is found to be altered in approximately 20% of cancers. Within the spectrum of renal cell carcinoma (RCC), KRAS mutations are rare, affecting 1% of cases and have been mainly associated with “papillary renal neoplasms with reverse polarity” (PRNRP), an emerging histologic subtype that is typically indolent, with a favorable prognosis. While KRAS mutations are identified at high frequency in PRNRP, their existence in a broader spectrum of diseases is unknown. We thus sought to explore the clinical correlates and prognostic significance of KRAS-mutant RCC in a single center cohort.

Methods:

All patients with RCC and KRAS mutations between 2006 and 2024 from a single large academic institution were identified. We conducted a retrospective chart review from the institutional EMR and analyzed previously sequenced tumor samples. Three patients were excluded from the study due to either lack of genomic data or indeterminate histology. A descriptive analysis was subsequently performed evaluating histology sub-type, metastatic status, receipt of systemic therapies, and mutation profiling.

Results:

13 patients with RCC and a KRAS mutation were included in this study. Patients had a median tumor size of 4.8 cm with most patients presenting at pT3a (n=5). Median age was 66 years (IQR=15), 77% were men (n=10). The predominant KRAS mutations were G12D (46%) and G12V (31%), with no germline alterations detected. Although most patients had localized tumors (n=8), only two were compatible with PRNRP. Five patients exhibited synchronous metastatic disease, while two developed metastases subsequently. The patients with an aggressive clinical course, had primary tumors with high nuclear grade, sarcomatoid/rhabdoid differentiation, and unclassified histology. These patients also had a higher rate of concomitant genomic alterations as seen in Figure 1.

Conclusion:

Though KRAS mutations in RCC have been associated with localized, indolent tumors, we identified a subset of patients with a complex mutational profile and aggressive disease characteristics. This finding highlights the need for better characterization of prognostic markers of KRAS mutations within RCC, which may help guide treatment selection and improve clinical outcomes in these patients. In addition, the emergence of KRAS-targeted therapies offers a potential new treatment option for this patient population. 

Funding: N/A