Mutations in thep16 gene in DMBA-induced pancreatic intraepithelial neoplasia and pancreatic cancer in rats

摘要

BACKGROUND: 7, 12-dimethylbenzanthracene (DMBA)-induced pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer in rats provide a classic model for uncovering the molec-ular mechanisms underlying pancreatic cancer. However, this model has not been characterized genetically, and in particular, the major genetic alterations in the p16 gene are unknown. n METHODS: Lesions of PanIN and pancreatic cancer were in-duced with DMBA implantation in 40 rats, and control pancre-atic tissue was obtained from 10 age-matched rats without ex-posure to DMBA. Pancreatic tissue was harvested three months after DMBA implantation and DNA was extracted. Homozy-gous deletions and point mutations of the p16 (exons 1 and 2) gene were detected by PCR ampliifcation and direct sequencing. n RESULTS: DMBA implantation in the 40 rats induced 26 Pan-INs and 9 carcinomas. The overall frequency of p16 alterations in the pancreatic tissue of these rats was 42.86% (15/35), and the changes were point mutations, not homozygous deletions. p16 mutations were present in 30.77% (8/26) of the rats with PanIN and 77.78% (7/9) of the rats with carcinoma (P<0.05). The increasing incidence of p16 alterations was detected in 20.00% (1/5) of PanIN-1, 28.57% (2/7) of PanIN-2 and 35.71% (5/14) of PanIN-3 lesions. n CONCLUSION: Our ifndings indicated that p16 alteration is a common event in the carcinogenesis of this model and that the mutation pattern is analogous to that of human lesions.