Genome scanning with array CGH delineates regional alterations in mouse islet carcinomas

Carcinomas that develop in the pancreatic islets of transgenic mice express ing the SV40 T-antigens (Tag) under transcriptional control of the rat insu lin II promoter (RIP) progress through well-characterized stages that are s imilar to aspects of human tumor progression, including hyperplastic growth , increased angiogenesis and reduced apoptosis'. The latter two stages have been associated with recurrent loss of heterozygosity (LOH)(2) and reduced genome copy number(3) on chromosomes 9 (LOH9) and 16 (LOH16), aberrations which we believe contribute to these phenotypes. Earlier analyses localized LOH9 to approximately 3 Mb and LOH16 to approximately 30 Mb (both syntenic with human 3q21-q25) but were limited by low throughput and a lack of info rmative polymorphic markers. Here we show that comparative genomic hybridiz ation to DNA microarrays (array CGH)(4-7) overcomes these limitations by al lowing efficient, genome-wide analyses of relative genome copy number. The CGH arrays used in these experiments carried BACs distributed at 2-20-MB in tervals across the mouse genome and at higher density in regions of interes t. Using array CGH, we further narrowed the loci for LOH9 and LOH16 and def ined new or previously unappreciated recurrent regions of copy-number decre ase on chromosomes 6, 8 and 14 (syntenic with human chromosomes 12p11-p13, 16q24.3 and 13q11-q32, respectively) and regions of copy-number increase on chromosomes 2 and 4 (syntenic to human chromosomes 20q13.2 and 1p32-p36, r espectively). Our analyses of human genome sequences syntenic to these regi ons suggest that CYP24, PFDN4, STMN1, CDKN1B, PPP2R3 and FSTL1 are candidat e oncogenes or tumor-suppressor genes. We also show that irradiation and ge netic background influence the spectrum of aberrations present in these tum ors.