PARENT SESSION
1:30 PM to 3:30 PM
Monday, April 22, 2002
Poster Session 11 Tumor Biology
Room: Nevada Exhibition Center

(P16-150) Gamma irradation alters both the frequency and the spectrum of recurrent genomic copy number aberrations in mouse islet carcinomas.

Hodgson, Graeme^*,1, Hager, Jeffrey², Hariono, Sujatmi¹, Albertson, Donna¹, Pinkel, Daniel¹, Collins, Colin¹, Hanahan, Douglas², Gray`, Joe¹, ¹ Comprehensive Cancer Center, San Francisco, CA² Department of Biochemistry and Biophysics, San Francisco, CA

ABSTRACT-
Carcinomas that develop in the pancreatic islets of transgenic mice expressing the SV40 T-antigens (Tag) progress through well-characterized stages that are similar to aspects of human tumor progression including hyperplastic growth, increased angiogenesis and reduced apoptosis. The latter two stages have been associated with recurrent losses of heterozygosity (LOH) and reduced genome copy number on chromosomes 9 (LOH9) and 16 (LOH16). We believe these aberrations encode genes that contribute to these phenotypes. We have used Comparative Genomic Hybridization to DNA microarrays (array CGH) for analyses of relative genome copy number at LOH9 and LOH16 to further refine these regions and facilitate gene identification. The CGH arrays used in these experiments carried Bacterial Artificial Chromosomes (BACs) distributed at 2-20 MB intervals across the mouse genome and at higher density in regions of interest. We tested the possibility that irradiation of tumor precursor cells would increase the frequency of informative copy number abnormalities by increasing the number of partial chromosome losses. We analyzed tumors from mice that received 600 rads of gamma irradiation at 6 weeks of age (when the mice had early hyperplastic, pre-angiogenic lesions but no solid tumors). Irradiation changed both the frequency and the spectrum of recurrent aberrations. The frequency of deletions involving LOH9 increased significantly in the irradiated mice, while the frequency of deletions involving LOH16 did not. In addition, gain of chromosome 4 occurred significantly less frequently in irradiated mice, whereas the frequency of loss of chromosome 14 increased after irradiation. This suggests that irradiation influences both the frequencies and locations of recurrent aberrations developed by these tumors. This finding supports the notion that environmental effects can alter the biology and genetics of tumor development. The unpredictable nature of the changes, however, will likely complicate efforts to use irradiation to facilitate positional localization of cancer genes by increasing the rate of partial chromosome losses; no partial losses were detected at LOH9 or LOH16 in the 15 irradiated tumors analyzed. However, array CGH will be applicable to investigation of radiation-induced genome alterations in tumors.

KEYWORDS: microarray, genomics, mouse, model