Involvement of mutations in the DPC4 promoter in endometrial carcinoma development.
To define the target of chromosome 18q loss of heterozygosity, which is prevalent in endometrial carcinomas, we made a deletion map from 64 tumors. Loss 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. DPC4 transcription was disturbed in all six of the tumors with deletions at 18q21.1 examined, which sharply contrasted with the positive transcription in 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 wild-type sequence of the DPC4 coding region instead of somatic mutations in the DPC4 coding region. We found a one- and two-base substitutions in the DPC4 promoter in two of the six tumors that showed disturbed DPC4 transcription. Chloramphenicol acetyltransferase assays clearly demonstrated that the mutant promoters had the potential to suppress or silence DPC4 transcription, implicating the DPC4 gene in endometrial carcinoma.
Zhou
Y
Y
Department of Reproductive Physiology and Endocrinology, Medical Institute of Bioregulation, Kyushu Univeristy, Beppu, Oita, Japan.
Kato
H
H
Shan
D
D
Minami
R
R
Kitazawa
S
S
Matsuda
T
T
Arima
T
T
Barrett
J C
JC
Wake
N
N
D000483:Alleles; D001483:Base Sequence; D002872:Chromosome Deletion; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D050989:GATA2 Transcription Factor; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D019656:Loss of Heterozygosity; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D016324:Sequence Tagged Sites; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D005819:Genetic Markers; D012333:RNA, Messenger; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D014157:Transcription Factors