Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: A comprehensive survey

J. T. Park, N. Johnson, S. Liu, M. Levesque, Y. J. Wang, H. Ho, D. Huso, A. Maitra, M. J. Parsons, J. D. Prescott, S. D. Leach

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2801-2806
Number of pages6
JournalOncogene
Volume34
Issue number21
DOIs
StatePublished - May 21 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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