Involvement of mutations in the DPC4 promoter in endometrial carcinoma development

To define the target of chromosome 18q loss of heterozygosity, which is pre valent in endometrial carcinomas, we made a deletion map from 64 tumors. Lo ss of heterozygosity on 18q was found in 20 tumors. Among these, 14 tumors carried deletions at the 18q21.1 region, where the DPC4 gene is located. DP C4 transcription was disturbed in all six of the tumors with deletions at 1 8q21.1 examined, which sharply contrasted with the positive transcription i n 12 tumors that retained heterozygosity at the 18q21.1 region. However, in the 14 tumors with the 18q21.1 deletions, the remaining allele had the wil d-type sequence of the DPC4 coding region instead of somatic mutations in t he DPC4 coding region. We found a one- and two-base substitutions in the DP C4 promoter in two of the six tumors that showed disturbed DPC4 transcripti on. Chloramphenicol acetyltransferase assays clearly demonstrated that the mutant promoters had the potential to suppress or silence DPC4 transcriptio n, implicating the DPC4 gene in endometrial carcinoma. (C) 1999 Wiley-Liss, Inc.