Oncogene Expression and Genetic Background Influence the Frequency of DNA Copy Number Abnormalities in Mouse Pancreatic Islet Cell Carcinomas

Jeffrey H. Hager, J. Graeme Hodgson, Jane Fridlyand, Sujatmi Hariono, Joe W. Gray, Douglas Hanahan

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

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 C57B1/6 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.

Original languageEnglish (US)
Pages (from-to)2406-2410
Number of pages5
JournalCancer Research
Volume64
Issue number7
DOIs
StatePublished - Apr 1 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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