Consistent allelic loss on mouse chromosome 7 distal to tyrosinase in 4-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-nitroquinoline-1-oxide (4NQO) eventually develop oral cavity squamous cell carcinomas, and two-thirds of these tumors have Ha-ras-1 (Hras1) point mutations at codon 12. Half of the tumors with Hras1 mutations have loss of heterozygosity (LOH) at Hras1. In the study reported here, seven tumors with LOH at Hras1, six heterozygous for Hras1, and six without Hras1 mutations were analyzed to define the extent of LOH on chromosome (Chr) 7. Microsatellite polymorphisms present in CBA/J mice were used as informative allelic markers. Tumors with LOH at Hras1 showed consistent 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 Hras1 or had no Hras1 mutations had evidence of chromosomal loss involving Chr 7. Because LOH was only detected in advanced lesions long after exposure to 4NQO had ceased, we presume that the chromosomal alterations by which LOH occurred were independent of the carcinogen exposure. The development of LOH in only half of the tumors with Hras1 point mutations suggests that LOH was not caused by the initial Hras1 point mutation but was a highly selected event during tumorigenesis.

Frequent DNA polymorphisms exist in inbred CBA/J and C3H/HeN mice.

Although occasional DNA polymorphisms have been observed in inbred mice, CBA/J and C3H/HeN mice have two microsatellite alleles at over 1/3 of microsatellite loci tested. Since DNA polymorphisms were not detected in DBA/2J, C57BL/6J, and BALB/cJ, the frequency of microsatellite polymorphisms appears to be strain specific. Thus, genetic studies in inbred mice require testing for preexisting polymorphisms. The polymorphisms detected in CBA/J mice appear to be stable and do not represent microsatellite instability or a mutator phenotype. Somatic mosaicism was not observed and no more than two alleles were detected per locus. CBA/J propagated only by brother-sister mating maintained seven of eight polymorphisms over 5 years. These data suggest that the polymorphisms are due to an inherited trait and that the pattern of inheritance is not due to Mendelian distribution. As breeding analysis was not performed, the pattern of allelic inheritance is unknown.