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 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.
Highlights
Selected in tumors of ostensibly similar histological type may be influenced by polymorphic variation of modifier genes between individuals and/or variation between individuals in the timing and type of carcinogenic insult
Nascent solid tumors formed in both models 10 –14 weeks after the onset of oncogene expression, with mice eventually succumbing to hypoglycemia as a result of a vast increase in  cell mass
That progression to the FVB) tumors than in RIP1Tag5/C3H tumors. It would appear invasive phenotype in this model is not the selection and that the microenvironment and/or physiology of the oncogeneoutgrowth of tumor cells that have high levels of Tag expression but expressing  cells impart different constraints on the developing rather represents a distinct stage of malignant progression defined by tumors that are relieved by distinct genomic alterations, with CNL6 secondary events, the molecular components of which have, at least in favoring the tumors whose pathway initiated in isolated oncogenepart, been characterized [18, 19]
Summary
Selected in tumors of ostensibly similar histological type may be influenced by polymorphic variation of modifier genes between individuals and/or variation between individuals in the timing and type of carcinogenic insult. We used the RIP-Tag model of pancreatic islet cell carcinogenesis [8] because our earlier studies indicated that the composition of recurrent aberrations in these tumors was influenced by genetic background and carcinogen exposure [9].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
