Genomewide assessment of genetic alterations in DMBA-induced rat sarcomas:Cytogenetic, CGH, and allelotype analyses reveal recurrent DNA copy numberchanges in rat chromosomes 1, 2, 4, and 7

Rat sarcomas, induced by subcutaneous injections of 7,12-dimethylbenz[a]ant hracene (DMBA), were studied with the objective of identifying critical chr omosome regions associated with tumorigenesis. We employed three genomewide screening techniques-cytogenetics, CGH, and allelotyping-in 19 DMBA-induce d sarcomas in FI (BN/Han x LE/Mol) rats. The most conspicuous finding in th e cytogenetic analysis was a high incidence of trisomy for rat chromosome 2 (RNO2). Signs of gene amplification (hsr) were also seen in several tumors . The CGH analysis revealed that gains in copy number were much more common than losses. The gains mostly affected RNO2 (10/19), RNO12q (7/19), and RN O19q (5/19), as well as the proximal part of RNO4 (8/19) and the distal par t of RNO7 (7/19). Reduction in copy number was seen in RNO17 (2/19). For th e allelotyping, we used 318 polymorphic microsatellite marker loci covering the entire genome. We identified regions of allelic imbalance affecting mo st of the rat chromosomes. The highest incidences of recurrent allelic imba lance were observed at loci in certain regions in RNO1, 2, 4, and 7 and at lower incidences in parts of RNO12, 16, 18, and 19. The combined results su ggested that genetic alterations detected in RNO2 and RNO12 usually corresp onded to complete or partial trisomy, whereas those in RNO1 and RNO7 seemed to involve regional deletions and/or gains. Furthermore, we could confirm that co-py number gains occur proximally in RNO4, where a previous study sh owed amplification of the Met oncogene in a subset of these tumors. Genes C hromosomes Cancer 28: 184-195, 2000. (C) 2000 Wiley-Liss, Inc.