ALLELOTYPE ANALYSIS OF MOUSE LUNG CARCINOMAS REVEALS FREQUENT ALLELICLOSSES ON CHROMOSOME-4 AND AN ASSOCIATION BETWEEN ALLELIC IMBALANCES ON CHROMOSOME-6 AND K-RAS ACTIVATION

We generated allelotypes of 38 methylene chloride-induced lung carcino mas from female C57BL/6J x C3H/HeJ F-1 (hereafter called B6C3F(1)) mic e. Two or more polymorphic markers per autosome, most of them microsat ellites, were examined for loss of heterozygosity. Allelic losses thro ughout the genome were generally infrequent except for markers on chro mosome 4, which were lost in approximately one-half of the carcinomas. Analysis of lung adenomas indicated that chromosome 4 toss was associ ated with malignant conversion. In addition, chromosome 4 loss was spe cific for Lung carcinomas based on comparison to methylene chloride-in duced liver tumors and additional studies of lung tumors from a variet y of treatment protocols and different mouse strains. preferential los s of the maternal chromosome 4 was observed in B6C3F(1) carcinomas. An alyses of additional tumors induced in mice from two reciprocal crosse s, A/J x C3H/HeJ F-1 (hereafter called AC3F(1)) and C3H/HeJ x A/J F-1 (hereafter called C3AF(1)), provided evidence for the inactivation of one allele of the putative chromosome 4 tumor suppressor gene by paren tal imprinting. Most B6C3F(1) tumors lost all chromosome 4 markers exa mined, suggesting nondisjunction events. In contrast, several C3AF(1) and AC3F(1) tumors appeared to have interstitial deletions that define d the smallest region of overlap as a 9 cM interval between Ifa-2 and D4Nds2. The homologous region on human chromosome 9p21-22 is frequentl y lost in a variety of tumors including lung cancers. A candidate tumo r suppresser gene, MTS1, is located in this region, which is homozygou sly deleted or mutated in cell Lines derived from a variety of human t umors. Finally, an association between K-ras gene activation and allel ic imbalances on chromosome 6 was observed for B6C3F(1) lung tumors.