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Carcinogenesis Advance Access published online on November 6, 2003
Carcinogenesis, doi:10.1093/carcin/bgh007
© 2003 by Oxford University Press
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© 2003 Oxford University Press

CARCINOGENESIS

Frequent p16INK4A/CDKN2A alterations in chemically induced syrian golden hamster pancreatic tumors

Junan Li 1, Christopher M. Weghorst 2, Masahiro Tsutsumi 3, Ming J. Poi 4, Thomas J. Knobloch 5, Bruce C. Casto 5, W. Scott Melvin 6, Ming-Daw Tsai 7, and Peter Muscarella 8*

1 Department of Surgery, The Ohio State University, Columbus, OH 43210, USA
2 Division of Environmental Health Sciences and Comprehensive Cancer Center, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43210, USA
3 Department of Oncological Pathology, Cancer Center, Nara Medical University, 840 Shijo-cho, Kashihara Nara 634-8521, Japan
4 Departments of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA
5 Division of Environmental Health Sciences, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43210, USA
6 Department of Surgery and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
7 Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Departments of Chemistry and Biochemistry The Ohio State University, Columbus, OH 43210, USA
8 Department of Surgery, The Ohio State University, Columbus, OH 43210, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA

* Corresponding author. E-mail: muscarella-1{at}medctr.osu.edu.

Received 16 July 2003 ; revised 12 September 2003 ; accepted 19 October 2003

Abstract

The p16INK4A/CDKN2A (p16) tumor suppressor gene is known to be inactivated in up to 98% of human pancreatic cancer specimens. Chemically induced pancreatic tumors in Syrian golden hamsters have been demonstrated to share many morphological and biological similarities with human pancreatic tumors and represent a potentially suitable model for the evaluation of therapies targeting p16. The purpose of this study was to evaluate primary hamster pancreatic tumor specimens for potentially inactivating p16 alterations. Tumors were induced with N-nitroso-bis-(2-oxopropyl) amine, followed by two cycles of augmentation pressure, and were harvested on day 100. Foci of tumor cells were identified by light microscopy after staining with hematoxilyn and eosin, and corresponding tumor tissues were excised for DNA extraction. The techniques of multiplex real-time PCR, direct sequencing, and methylation-specific PCR were used to evaluate 30 tumor specimens for homozygous deletions, mutations, and aberrant methylation of 5' CpG islands, respectively. Homozygous deletions were identified in 11 of 30 (36.7%) specimens, mutations were identified in 4 of 30 (13.3%) specimens, and aberrant methylation of 5' CpG islands was found in 14 of 30 (46.7%) specimens. The overall frequency of p16 alterations was 93.3% (28 of 30 specimens) and the majority of changes (83.3%) were noted to be secondary to methylation or homozygous deletion. The four mutations significantly impaired cyclin-dependent kinase 4 inhibitory activity, and two resulted in perturbation of the global structure of P16 protein. These findings indicate that p16 inactivation is a common event in chemically induced hamster tumors, and that this animal model is appropriate for comparative studies evaluating pancreatic cancer therapeutic strategies targeting p16.

p16, Syrian Golden hamster, pancreatic cancer
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