title: Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: A comprehensive survey.
abstract: Somatic activation of the KRAS proto-oncogene is evident in almost all pancreatic cancers, and appears to represent an initiating event. These mutations occur primarily at codon 12 and less frequently at codons 13 and 61. Although some studies have suggested that different KRAS mutations may have variable oncogenic properties, to date there has been no comprehensive functional comparison of multiple KRAS mutations in an in vivo vertebrate tumorigenesis system. We generated a Gal4/UAS-based zebrafish model of pancreatic tumorigenesis in which the pancreatic expression of UAS-regulated oncogenes is driven by a ptf1a:Gal4-VP16 driver line. This system allowed us to rapidly compare the ability of 12 different KRAS mutations (G12A, G12C, G12D, G12F, G12R, G12S, G12V, G13C, G13D, Q61L, Q61R and A146T) to drive pancreatic tumorigenesis in vivo. Among fish injected with one of five KRAS mutations reported in other tumor types but not in human pancreatic cancer, 2/79 (2.5%) developed pancreatic tumors, with both tumors arising in fish injected with A146T. In contrast, among fish injected with one of seven KRAS mutations known to occur in human pancreatic cancer, 22/106 (20.8%) developed pancreatic cancer. All eight tumorigenic KRAS mutations were associated with downstream MAPK/ERK pathway activation in preneoplastic pancreatic epithelium, whereas nontumorigenic mutations were not. These results suggest that the spectrum of KRAS mutations observed in human pancreatic cancer reflects selection based on variable tumorigenic capacities, including the ability to activate MAPK/ERK signaling.
authors: Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors: J T
authors: JT
authors: Park
authors: Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors: N
authors: N
authors: Johnson
authors: Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors: S
authors: S
authors: Liu
authors: Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors: M
authors: M
authors: Levesque
authors: Graduate Program in Human Genetics, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors: Y J
authors: YJ
authors: Wang
authors: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors: H
authors: H
authors: Ho
authors: Department of Molecular & Comparative Pathobiology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors: D
authors: D
authors: Huso
authors: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors: A
authors: A
authors: Maitra
authors: 1] Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA [2] Graduate Program in Human Genetics, Johns Hopkins Medical Institutions, Baltimore, MD, USA [3] Institute of Genetic Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors: M J
authors: MJ
authors: Parsons
authors: Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors: J D
authors: JD
authors: Prescott
authors: 1] Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA [2] Graduate Program in Human Genetics, Johns Hopkins Medical Institutions, Baltimore, MD, USA [3] Institute of Genetic Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors: S D
authors: SD
authors: Leach
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D004848:Epithelium / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010179:Pancreas / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D014714:Vertebrates / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins