Multiple genetic alterations in hamster pancreatic ductal adenocarcinomas.
Pancreatic ductal adenocarcinomas induced in the Syrian golden hamster (SGH) by N-nitrosobis(2-oxopropyl)amine share many similarities with the human disease, including mutations of the K-ras oncogene. In vitro carcinogenesis studies with immortal SGH pancreatic duct cells indicate that neoplastic transformation in this system can occur without mutational inactivation of p53 suppressor gene. In this study we extend the genetic analysis of the in vivo SGH model to increase the number of cases analyzed for the status of K-ras and to determine further the spectrum of alterations involved; we have studied the status of the p53, DCC, and Rb-1 suppressor genes and the status of the mdm2 oncogene, which can involve p53 indirectly. The partial SGH-coding sequence of mdm2 and DCC was determined. K-ras mutation in the second position of codon 12 was present in 17 of 19 (90%) of tumors. Immunohistochemistry and single strand conformation polymorphism analysis showed no evidence of p53 mutation in 21 tumors. RNase protection assays showed overexpression of mdm2 in 5 of 19 (26%) tumors. Semiquantitative reverse transcription-PCR analysis showed a complete or partial loss of DCC expression in 10 of 19 (53%) neoplasms and of Rb-1 (42%) expression in 8 of 19 tumors when compared to matched controls. Deregulation of these genes appears to be significant in SGH pancreatic carcinogenesis as indicated by their frequencies. However, the fact that 6 tumors showed either only a K-ras mutation or the absence of alterations of the 5 genes analyzed indicates that additional as yet unstudied or unknown genes are also involved in SGH pancreatic duct carcinogenesis.
Chang
K W
KW
Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Laconi
S
S
Mangold
K A
KA
Hubchak
S
S
Scarpelli
D G
DG
D000818:Animals; D001483:Base Sequence; D002273:Carcinogens; D018270:Carcinoma, Ductal, Breast / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D003001:Cloning, Molecular; D006224:Cricetinae; D017931:DNA Primers; D018076:DNA, Complementary; D005091:Exons; D017353:Gene Deletion; D016161:Genes, Retinoblastoma; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D008647:Mesocricetus; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009602:Nitrosamines; D009687:Nuclear Proteins; D009857:Oncogenes; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D017386:Sequence Homology, Amino Acid
D002273:Carcinogens; D017931:DNA Primers; D018076:DNA, Complementary; D009602:Nitrosamines; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C013622:nitrosobis(2-oxopropyl)amine; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2