INTRAGENIC MUTATIONS OF CDKN2B AND CDKN2A IN PRIMARY HUMAN ESOPHAGEALCANCERS

The CDKN2A and CDKN2B genes, encoding p16 and p15 respectively, are lo cated on chromosome 9p21, a locus at which frequent homozygous and het erozygous deletions occur in many primary human tumors, including esop hageal carcinoma. CDKN2A and CDKN2B inhibit cyclin dependent kinase 4 (CDK4) and CDK6 and control cellular proliferation by preventing entry into the S phase of the cell cycle. Their inactivation may contribute to uncontrolled growth in human cancer. We previously described CDKN2 A exon 2 mutations in a pilot study of 43 esophageal cancers. In order to determine whether CDKN2A and CDKN2B are frequent targets of 9p21 d eletion in esophageal carcinogenesis, we have now analyzed 60 primary esophageal cancers for mutations in both exons 1 and 2 of CDKN2A and C DKN2B by direct sequencing of PCR amplified genomic DNAs. In conjuncti on with our previously published data, we have identified a total of e ight nucleic acid substitutions among 60 esophageal carcinomas; here, we describe one new CDKN2B nonsense mutation and one new silent CDKN2B mutation that occurred somatically. Taken together, these results sug gest that intragenic mutations in CDKN2A and CDKN2B occur in esophagea l cancer, but that they are infrequent events. In view of the known hi gh frequency of loss of heterozygosity at the chromosome 9p21 locus in esophageal cancers, the current data suggest that intragenic mutation is not the predominant mode of inactivation of CDKN2A and CDKN2B or t hat other genes are targets of deletion at this locus in these cancers .