Oncogene expression and genetic background influence the frequency of DNA copy number abnormalities in mouse pancreatic islet cell carcinomas.
Quantitative measurements of tumor genome composition show remarkable heterogeneity in tumors arising from the same anatomical location and/or histopathological class and stage. The factors that contribute to genomic heterogeneity are not clear, but germ-line allelic variation and timing of initiating oncogenic events are likely candidates. We investigated these factors by using array comparative genomic hybridization to measure genomic aberrations in genetically engineered mouse models of pancreatic islet cell carcinoma, in which oncogenic transformation is elicited by the SV40 T antigens expressed under the control of the rat insulin promoter (RIP-Tag). Two distinct transgenic RIP-Tag lines, and three polymorphic sublines of one, enabled us to investigate the effects of genetic background and differing age of oncogene induction. Both parameters were found to bias the spectrum of genomic copy number abnormalities. Specifically, the frequency of losing portions of chromosomes 9 and 16 was significantly modulated by genetic background, with the former being lost at highest rates in the FVB/N background and the latter being lost to greatest extent in both FVB/N and C57Bl/6 tumors compared with C3HeB/Fe tumors. The frequency of losing a region of chromosome 6 varied according to the age when tumorigenesis was initiated; loss of chromosome 6 was significantly higher when oncogene expression was first activated in adulthood. These studies illustrate the utility of transgenic animal models for investigation of factors influencing genomic heterogeneity despite the commonalty of target cell type and initiating oncogene.
Hager
Jeffrey H
JH
Department of Biochemistry, University of California at San Francisco Diabetes and Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94143, USA.
Hodgson
J Graeme
JG
Fridlyand
Jane
J
Hariono
Sujatmi
S
Gray
Joe W
JW
Hanahan
Douglas
D
D000818:Animals; D018273:Carcinoma, Islet Cell / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009693:Nucleic Acid Hybridization; D009857:Oncogenes / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics*
D004273:DNA, Neoplasm