Clinical and Molecular Characterization of KRAS Mutations in Renal Cell Carcinoma

KRAS mutations in renal cell carcinoma (RCC) are rare and are associated with the histologic subtype "papillary renal neoplasm with reverse polarity" (PRNRP). Despite this association, the broader clinical and molecular implications of KRAS mutation in RCC are not well understood. This study aimed to characterize the clinical and molecular features of KRAS-mutated RCC. KRAS-mutant RCC patients were identified within the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) and The Cancer Genome Atlas Kidney Renal Papillary Cell Carcinoma (TCGA-KIRP) repository. Fraction and allele-specific copy number estimates from tumor sequencing (FACETS) was performed to obtain copy number alterations. Available samples were used for immunohistochemistry and RNA-sequencing analysis. Seventeen patients were included. Three distinct KRAS-mutant RCC subtypes were identified: KRAS-mutant PRCC (35%), KRAS-mutant URCC (35%), and PRNRP (29%). Seven patients (41%) had metastatic disease; none were PRNRP. RNAseq-based deconvolution analysis revealed that PRNRP had enrichment in distal nephron components, whereas KRAS-mutant PRCC was enriched in proximal tubule cells (p = 0.02). IHC staining of L1CAM was positive in PRNRP but negative in KRAS-mutant PRCC, supporting their distinct cell-of-origin phenotypes. This study is limited by its cohort size, which influences the availability of tissue samples. PRNRP represents a distinct KRAS-mutant RCC subtype with unique metabolic and genomic features linked to its distal nephron origin. This contrasts with the genomic complexity and aggressive clinical behavior observed in KRAS-mutant PRCC and URCC, highlighting the need for subtype-specific diagnostic criteria and therapeutic strategies.