2 VARIANTS OF THE CIP1 WAF1 GENE OCCUR TOGETHER AND ARE ASSOCIATED WITH HUMAN CANCER/

Several groups have recently isolated and characterized an inhibitor o f cyclin-dependent kinases, p21(CIP1/WAF1) which is transcriptionally induced by wild-type but not mutant p53, It is likely that p21(CIP1)/( WAF1) mediates the growth suppression effects of p53 by arresting the cell cycle at the G(1)/S checkpoint, and by inducing apoptosis, To tes t the hypothesis that primary human tumors have mutations in the CIP1/ WAF1 gene which propagates the carcinogenic process, we examined prima ry breast and sarcoma tumor specimens for alterations in the CIP1/WAF1 gene, Unique, or acquired somatic mutations were not observed indicat ing that they are not selected for during the carcinogenic process; ho wever, two common variants were identified, The variants were not uniq ue to tumors as 10.7% of normal individuals exhibited the variants, No netheless, the frequency of the variants in tumors with wild-type p53 (20.4%) was significantly greater (p = 0.05) than in normal DNAs, In c ontrast, the frequency of the variants (4.1%) was found to be signific antly lower in tumors with p53 mutations (p = 0.006), These data sugge st that the occurrence of the variants may have a direct effect on tum or development and may, in some cases, be incompatible with p53 mutati ons.