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Analysis of Specific Gene Mutations in the Transforming Growth Factor-ß Signal Transduction Pathway in Human Ovarian Cancer¹

Department of Obstetrics and Gynecology [D. W., T. K., H. M., F. T., Y. I.] and First Department of Surgery [A. M., Y. S.], Gunma University School of Medicine, Gunma 3715-811, Japan; Second Department of Surgery, Fukushima Medical University, Fukushima 960-1295, Japan [S. T.]; and Department of Reproductive Physiology and Endocrinology, Medical Institute of Bioregulation, Kyushu University, Ohita 874-0838, Japan [N. W.]

Several proteins, including transforming growth factor ß (TGF-ß) receptor type I (RI), TGF-ß receptor type II (RII), Smad2, Smad3, and Smad4/DPC4, have been identified in the transduction pathway of the tumor suppressor TGF-ß. Mutations in TGF-ß RI, TGF-ß RII, Smad2, and Smad4/DPC4 genes are associated with several human cancers. The present study examines these gene mutations in 32 human ovarian cancers and 14 patient-matched normal tissues. For the first time, mutations in the Smad2 and Smad4 genes were analyzed in relation to human ovarian cancer. Gene mutations of TGF-ß RI, TGF-ß RII, Smad2, and Smad4 were analyzed using specific primers by PCR-single-strand conformational polymorphism (SSCP), and the results revealed a frameshift mutation at codons 276–277 (CTCTGGCTGCGTGG) in exon 5 of TGF-ß RI in 10 of 32 tumor samples (31.3%). This mutation was associated with reduced or absent expression of TGF-ß RI protein and p53 protein in tumor tissues. We detected SSCP variants of TGF-ß RII in exon 2 in 20 of 32 tumors. Sequence analysis of these variants revealed an A to G transition at the seventh band of intron 2. In this A to G polymorphism in intron 2, 12 samples (37.5%) had A/A alleles, 12 (37.5%) had A/G alleles, and 8 (25%) had G/G alleles. We detected Smad2 SSCP variants in exon 4 in 12 of 32 tumors (37.5%). Sequence analysis revealed a 2-bp deletion in the polypyrimidine tract of intron 3, which is located at position -39 to -56 in the splice acceptor site of the intron 3-exon 4 junction. No SSCP variants were detected in the Smad4 gene. These findings suggest that mutations in the TGF-ß RI and in its signal transduction pathway are likely responsible for human ovarian carcinogenesis.

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