GENETIC ALTERATIONS IN MOUSE LUNG-TUMORS - IMPLICATIONS FOR CANCER CHEMOPREVENTION

Specific genetic alterations affecting known tumor suppressor genes an d proto-oncogenes occur during mouse lung tumorigenesis. These include mutational activation of the K-ras gene, commonly seen at. a frequenc y of about 80% in both spontaneously occurring and chemically induced adenomas and adenocarcinomas of the lung, suggesting that it is an ear ly event that persists into malignancy. Allelic loss of the p16 tumor suppressor gene also is a frequent event, occurring in about 50% of mo use lung adenocarcinomas, but rarely in lung adenomas, suggesting that it may play a role in malignant conversion or progression of lung tur ners. Other genetic alterations detected in mouse lung tumors include reduced expression of Rb and p16, and increased c-myc expression. Alte rations of these genes are also common in the genesis of human lung ca ncer. Genetic linkage analysis to identify human lung cancer susceptib ility genes is difficult due to the genetic heterogeneity and exposure to environmental risk factors. The mouse lung tumor model has become a valuable alternative for identifying such genes. Recently, loci resp onsible for mouse lung tumor susceptibility have been mapped to chromo somes 6, 9, 17, and 19, while those linked to lung tumor resistance ha ve been mapped to chromosomes 4, 11, 12, and 18. Known candidate susce ptibility or resistance genes include the K-ras proto-oncogene on chro mosome 6, and the p16 tumor supressor gene on chromosome 4. With evide nce of considerable overlap between the genetic alterations that under lie human and mouse lung tumorigenesis, the mouse lung tumor model has been expanded to include pre-clinical screening of chemopreventive ag ents against human lung cancer. Studies on the modulation of genetic d efects in mouse lung tumors by known and potential chemopreventive age nts should further the goal of developing an effective prevention and treatment of lung cancer. (C) 1998 Wilev-Liss, Inc.