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Tumor Suppressor Loci on Mouse Chromosomes 9 and 16 Are Lost at Distinct Stages of Tumorigenesis in a Transgenic Model of Islet Cell Carcinoma¹

Hormone Research Institute, Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California 94143-0534 [S. P., G. C., D. H.]; Center for Genome Research, Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142 [W. D., E. S. L.]; and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 [W. D., E. S. L.]

Techniques that detect loss of genetic heterozygosity (LOH) have helped elucidate genes involved in human cancers. Previously, a genomewide 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 3.2 centiMorgans on chromosome 9, syntenic with human chromosomes 3q and 15q.

¹ This research was supported by two grants from the National Cancer Institute, one to D. H. and another to Dr. Judah Folkman and D. H., and by grants (to E. S. L.) from the National Center for Human Genome Research and the Markey Foundation. Postdoctoral support was provided by the UCSF Molecular Medicine Program, the Burroughs-Wellcome Fund, and the UCSF Department of Surgery (all to S. P.), and the American Heart Association (to G. C.).

² Present address: Research Institute of Molecular Pathology, Dr. Bohr Gasse 7, A1030, Vienna, Austria.

³ To whom requests for reprints should be addressed, at Department of Biochemistry and Biophysics, Hormone Research Institute, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0534. Phone: (415) 476-9209; Fax: (415) 731-3612.

Received 7/ 7/95. Accepted 10/17/95.

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