Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer Journal Article
| Authors: | McIntyre, C. A.; Grimont, A.; Park, J.; Meng, Y.; Sisso, W. J.; Seier, K.; Jang, G. H.; Walch, H.; Aveson, V. G.; Falvo, D. J.; Fall, W. B.; Chan, C. W.; Wenger, A.; Ecker, B. L.; Pulvirenti, A.; Gelfer, R.; Zafra, M. P.; Schultz, N.; Park, W.; O'Reilly, E. M.; Houlihan, S. L.; Alonso, A.; Hissong, E.; Church, G. M.; Mason, C. E.; Siolas, D.; Notta, F.; Gonen, M.; Dow, L. E.; Jarnagin, W. R.; Chandwani, R. |
| Article Title: | Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer |
| Abstract: | 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. Copyright © 2024 Elsevier Inc. All rights reserved. |
| Keywords: | signal transduction; aged; middle aged; genetics; mutation; mortality; pancreatic neoplasms; mouse; animal; metabolism; animals; mice; carcinoma, pancreatic ductal; cell motion; immunoglobulin enhancer binding protein; pathology; pancreas tumor; nf-kappa b; cell movement; genomics; pancreatic cancer; kras; protein p21; proto-oncogene proteins p21(ras); kras protein, human; epithelial-mesenchymal transition; epithelial mesenchymal transition; pancreatic ductal carcinoma; clinical outcomes; humans; prognosis; human; male; female; organoids; organoid; spatial transcriptomics |
| Journal Title: | Cancer Cell |
| Volume: | 42 |
| Issue: | 9 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2024-09-09 |
| Start Page: | 1614 |
| End Page: | 1629.e5 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2024.08.002 |
| PUBMED: | 39214094 |
| PROVIDER: | scopus |
| PMCID: | PMC11419252 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Scopus |
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