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Allelotype Analysis of Mouse Lung Carcinomas Reveals Frequent Allelic Losses on Chromosome 4 and an Association between Allelic Imbalances on Chromosome 6 and K-ras Activation

Laboratories of Molecular Carcinogenesis [M. H., C. C., R. W.], Molecular Toxicology [T. D., M. A.], and Chemical Pathology [J. F., R. M.], National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, and Whitehead Institute for Biomedical Research, Center for Genome Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 [W. D., E. L.]

We generated allelotypes of 38 methylene chloride-induced lung carcinomas from female C57BL/6J x C3H/HeJ F₁ (hereafter called B6C3F₁) mice. Two or more polymorphic markers per autosome, most of them microsatellites, were examined for loss of heterozygosity. Allelic losses throughout the genome were generally infrequent except for markers on chromosome 4, which were lost in approximately one-half of the carcinomas. Analysis of lung adenomas indicated that chromosome 4 loss was associated with malignant conversion. In addition, chromosome 4 loss was specific for lung carcinomas based on comparison to methylene chloride-induced liver tumors and additional studies of lung tumors from a variety of treatment protocols and different mouse strains. Preferential loss of the maternal Chromosome 4 was observed in B6C3F₁ carcinomas. Analyses of additional tumors induced in mice from two reciprocal crosses, A/J x C3H/HeJ F₁ (hereafter called AC3F₁) and C3H/HeJ x A/J F₁ (hereafter called C3AF₁), provided evidence for the inactivation of one allele of the putative chromosome 4 tumor suppressor gene by parental imprinting. Most B6C3F₁ tumors lost all chromosome 4 markers examined, suggesting nondisjunction events. In contrast, several C3AF₁ and AC3F₁ tumors appeared to have interstitial deletions that defined the smallest region of overlap as a 9-cM interval between Ifa-2 and D4Nds2. The homologous region on human chromosome 9p21–22 is frequently lost in a variety of tumors including lung cancers. A candidate tumor suppressor gene, MTS1, is located in this region, which is homozygously deleted or mutated in cell lines derived from a variety of human tumors. Finally, an association between K-ras gene activation and allelic imbalances on chromosome 6 was observed for B6C3F₁ lung tumors.

¹ Present address: Institute of Neuropathology, University Hospital Zürich, CH-8091 Zürich, Switzerland. To whom requests for reprints should be addressed.

² Present address: St. Mary's Hospital, Grand Junction, CO 81501.

Received 7/ 1/94. Accepted 10/ 3/94.

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