Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer.

KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRAS(G12R) mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRAS(G12R) tumors are associated with decreased distant recurrence and improved survival as compared to KRAS(G12D). To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRAS(G12D) and increased nuclear factor κB (NF-κB) signaling in KRAS(G12R) tumors. Orthogonal studies of mouse Kras(G12R) PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.