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.