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 KRASG12R G12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRASG12R G12R tumors are associated with decreased distant recurrence and improved survival as compared to KRASG12D. 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 KRASG12D G12D and increased nuclear factor KB (NF-KB) signaling in KRASG12R G12R tumors. Orthogonal studies of mouse KrasG12R 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.