Cancer cell · 2024
Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer.
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McIntyre Caitlin A, Grimont Adrien, Park Jiwoon, Meng Yinuo, Sisso Whitney J, Seier Kenneth, Jang Gun Ho, Walch Henry, Aveson Victoria G, Falvo David J, Fall William B, Chan Christopher W, Wenger Andrew, Ecker Brett L, Pulvirenti Alessandra, Gelfer Rebecca, Zafra Maria Paz, Schultz Nikolaus, Park Wungki, O'Reilly Eileen M, Houlihan Shauna L, Alonso Alicia, Hissong Erika, Church George M, Mason Christopher E, Siolas Despina, Notta Faiyaz, Gonen Mithat, Dow Lukas E, Jarnagin William R, Chandwani Rohit
Аннотация
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 mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRASG12R tumors are associated with decreased distant recurrence and improved survival as compared to KRASG12D. 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 and increased nuclear factor κB (NF-κB) signaling in KRASG12R tumors. Orthogonal studies of mouse KrasG12R 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.