DELETION MAPPING OF A PUTATIVE TUMOR-SUPPRESSOR GENE ON CHROMOSOME-4 IN MOUSE LUNG-TUMORS

Genetic and molecular studies have implicated the region of the alpha-interferon gene cluster on mouse chromosome 4 as the location of a putative tumor suppressor gene. A region of homology on human chromosome 9p21-22 that is frequently deleted in multiple human cancers has recently been found to contain a candidate tumor suppressor gene called multiple tumor suppressor-1 (MTS1), which was previously shown to encode an inhibitor of cyclin-dependent kinase 4. We performed loss of heterozygosity and deletion analyses to map the most commonly deleted region on chromosome 4 in F-1 hybrid mouse lung tumors. Ten simple sequence length polymorphism markers were analyzed with focus on the alpha-interferon region. Allelic losses were detected in 29 of 61 (48%) of the lung adenocarcinomas but in only 1 of 38 (3%) of the lung adenomas examined. In most cases, the losses appeared to occur by nondisjunction. However, in three carcinomas, we detected homozygous deletions that overlapped at simple sequence length polymorphism marker D4MIT77. These data suggest a critical region of about 2 cM immediately distal to the alpha-interferon locus as the likely domain of a novel tumor suppressor gene on mouse chromosome 4, the loss of which appears to be involved in the progression of mouse lung tumorigenesis.