—3.2centiMorgans on chromosome 9, syntenic with human chromosomes 3q and lSq

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, Lohi 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 chromo somes 9 and 16. On chromosome 9, hyperplastic and early angiogeaic islets reveal a low rate of loss (<5%) indistinguIshablefrom 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 Lohi may contribute to the progression from the angiogenic stage to a solid tumor. Tumors containing chromosomes with partial LOH have allowed improved localization of Lohi to a region of —3.2centiMorgans on chromosome 9, syntenic with human chromosomes 3q and lSq.