Tumor suppressor loci on mouse chromosomes 9 and 16 are lost at distinct stages of tumorigenesis in a transgenic model of islet cell carcinoma.
Techniques that detect loss of genetic heterozygosity (LOH) have helped elucidate genes involved in human cancers. Previously, a genome-wide search using simple sequence length polymorphisms to detect LOH in islet cell tumors arising in a transgenic mouse model of multistage tumorigenesis had revealed two candidate tumor suppressor genes, Loh1 and Loh2, on chromosomes 9 and 16, respectively. We now have analyzed the early stages of tumor development in this model (hyperplastic, early angiogenic, and angiogenic islets) for LOH involving regions of chromosomes 9 and 16. On chromosome 9, hyperplastic and early angiogenic islets reveal a low rate of loss (< 5%) indistinguishable from background; angiogenic islets showed a 9% rate, whereas the final tumor stage had an 18% rate. By contrast, LOH was observed much earlier on chromosome 16. Notably, the LOH rate in angiogenic islets was 29%, comparable to the rate seen in end-stage tumors (32%). The results show that the two loci are lost preferentially at different stages of tumorigenesis. The observation that a high LOH rate at Loh2 is seen in the angiogenic islet stage suggests that this locus may contain an angiogenesis suppressor; in contrast, the later appearance of Loh1 may contribute to the progression from the angiogenic stage to a solid tumor. Tumors containing chromosomes with partial LOH have allowed improved localization of Loh1 to a region of approximately 3.2 centiMorgans on chromosome 9, syntenic with human chromosomes 3q and 15q.
Department of Biochemistry and Biophysics, University of California San Francisco 94143-0534, USA.
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Parangi
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Dietrich
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Christofori
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Lander
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Hanahan
D000818:Animals; D018273:Carcinoma, Islet Cell / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D004273:DNA, Neoplasm / Q000235:genetics; D016147:Genes, Tumor Suppressor; D005819:Genetic Markers; D006965:Hyperplasia / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D017384:Sequence Deletion
D004273:DNA, Neoplasm; D005819:Genetic Markers