LOSS OF HETEROZYGOSITY AT CHROMOSOME 1Q LOCI IN RAT MAMMARY-TUMORS

To better characterize abnormalities affecting rat chromosome 1 during mammary carcinogenesis, tumors were induced by nitrosomethylurea in F -1 hybrid rats polymorphic at multiple chromosome 1 loci. By means of restriction fragment length polymorphism and microsatellite length pol ymorphism analyses, we observed loss of heterozygosity or allelic imba lance affecting various loci on the q arm of chromosome 1 in a high pe rcentage of the 49 tumors analyzed. Fifty percent of the tumors showed loss or imbalance affecting the most distal (1q55) INS1 (rat insulin 1 gene) locus. The MT1Pa (metallothionein-1 pseudogene a) locus was ob served to be affected in 58% of tumors induced in BUF/NCr x ACI/Vsp ra ts. Most of the losses appeared to have occurred by mitotic recombinat ion. No parental bias was observed on the affected chromosome 1. Tumor s were a Iso screened for mutations in codon 12 of the Ha-ras-1 gene, which is located on 1q. We observed an association between the presenc e of mutation and allelic imbalance. These studies confirm our previou s cytogenetic observations of a high level of nonrandom instability af fecting rat chromosome 1 during mammary carcinogenesis. The observed l oss of heterozygosity may indicate the existence of a putative tumor s uppressor gene within the distal half of the 1q arm. These abnormaliti es, however, could also be related to the early stages of Ha-ras ampli fication. (C) 1995 Wiley-Liss, Inc.