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

Autor:	McIntyre CA; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Grimont A; Department of Surgery, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Park J; Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA., Meng Y; Department of Surgery, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA., Sisso WJ; Department of Surgery, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA., Seier K; Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Jang GH; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada., Walch H; Marie-Josee and Henry R Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Aveson VG; Department of Surgery, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Falvo DJ; Department of Surgery, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Fall WB; Department of Surgery, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA., Chan CW; Department of Surgery, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Wenger A; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of Medicine, Weill Cornell Medicine, New York, NY, USA., Ecker BL; Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA., Pulvirenti A; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Gelfer R; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA., Zafra MP; Department of Medicine, Weill Cornell Medicine, New York, NY, USA., Schultz N; Marie-Josee and Henry R Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Park W; Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; David M. Rubinstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., O'Reilly EM; Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; David M. Rubinstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Houlihan SL; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA., Alonso A; Department of Medicine, Weill Cornell Medicine, New York, NY, USA., Hissong E; Department of Pathology, Weill Cornell Medicine, New York, NY, USA., Church GM; Department of Genetics, Harvard Medical School, Boston, MA, USA., Mason CE; Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA; WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY, USA., Siolas D; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of Medicine, Weill Cornell Medicine, New York, NY, USA., Notta F; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada., Gonen M; Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Dow LE; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of Medicine, Weill Cornell Medicine, New York, NY, USA., Jarnagin WR; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; David M. Rubinstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Chandwani R; Department of Surgery, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; David M. Rubinstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA. Electronic address: roc9045@med.cornell.edu.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2024 Sep 09; Vol. 42 (9), pp. 1614-1629.e5. Date of Electronic Publication: 2024 Aug 29.
DOI:	10.1016/j.ccell.2024.08.002
Abstrakt:	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. Competing Interests: Declaration of interests E.M.O., research funding: Genentech/Roche, BioNTech, AstraZeneca, Arcus, Elicio, Parker Institute, NIH/NCI, Pertzye; consulting/DSMB: Boehringer Ingelheim, BioNTech, Ipsen, Merck, Novartis, AstraZeneca, BioSapien, Astellas, Thetis, Autem, Novocure, Neogene, BMS, Tempus, Fibrogen, Merus, Agios (spouse), Genentech-Roche (spouse), Eisai (spouse). G.M.C.:A full listing of G.M.C.’s interests can be found at http://arep.med.harvard.edu/gmc/tech/html. C.E.M., founder: Onegevity, Twin Orbit, and Cosmica Biosciences; consulting: Nanostring. L.E.D., research funding/consulting: Revolution Medicines; scientific advisory board: Mirimus. R.C., research funding: Sanofi; consulting/DSMB: Boston Scientific. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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