CONSISTENT ALLELIC LOSS ON MOUSE CHROMOSOME-7 DISTAL TO TYROSINASE IN4-NITROQUINOLINE-1-OXIDE-INDUCED ORAL CAVITY TUMORS WITH LOSS OF HETEROZYGOSITY AT HA-RAS-1

We have previously shown that all CBA/J mice exposed to 4-nitroquinoli ne-1-oxide (4NQO) eventually develop oral cavity squamous cell carcino mas, and two-thirds of these tumors have Ha-ras-1 (Hras1) point mutati ons at codon 12. Half of the tumors with Hras1 mutations have loss of heterozygosity (LOH) at Hras1. In the study reported here, seven tumor s with LOH at Hras1, six heterozygous for Hras1, and six without Hras1 mutations were analyzed to define the extent of LOH on chromosome (Ch r) 7. Microsatellite polymorphisms present in CBA/J mice were used as informative allelic markers. rumors with LOH at Hras1 showed consisten t allelic loss at the distal portion of Chr 7. The boundary of allelic loss lay between the tyrosinase and hemoglobin beta chain loci, which are 6 cM apart. None of the tumors that remained heterozygous for Hra s1 or had no Hras1 mutations had evidence of chromosomal loss involvin g Chr 7. Because LOH was only detected in advanced lesions long after exposure to 4NQO had ceased, we presume that the chromosomal alteratio ns by which LOH occurred were independent of the carcinogen exposure. The development of LOH in only half of the tumors with Hras1 point mut ations suggests that LOH was not caused by the initial Hras1 point mut ation but was a highly selected event during tumorigenesis. (C) 1997 W iley-Liss, Inc.