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Division of Clinical Genetics, Department of Medical Genetics, Biomedical Research Center, Osaka University Medical School, Osaka 565-0871 [Y. M., K. I., Y. Nag., T. A., Y. Nak.]; Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-0025 [Y. S., S. I.]; Department of Surgery, Municipal Ikeda Hospital, Osaka 563-8510 [M. M., T. S.]; and Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639 [Y. Nak.], Japan
We screened 75 primary hepatocellular carcinomas for somatic mutations in the entire coding region of the ß-catenin gene. We detected somatic mutations in 14 tumors; 12 were considered to cause amino acid substitutions and 2 were interstitial deletions of 51 or 195 nucleotides of genomic DNA, corresponding to exon 3. Among the 12 point mutations, 6 occurred at potential serine/threonine phosphorylation residues of codons 33, 41, or 45. The remaining six tumors contained a mutation at codon 32 (aspartic acid) or 34 (glycine), flanking to the serine residue at codon 33. By Western blot analysis, we confirmed accumulation of ß-catenin in five tumors for which frozen tissues were available; the five included tumors in which amino acid alterations had occurred at codons 32, 34, or 45, and one with a 17-amino acid deletion. Our results suggested that accumulation of ß-catenin due to amino acid substitutions at potential serine/threonine phosphorylation residues or at their neighboring codons or interstitial deletions involving exon 3 could contribute to hepatocellular carcinogenesis.
1 This work was supported in part by a special grant for Strategic Advanced Research on Cancer from the Ministry of Education, Culture, Sports, and Science of Japan and by Research for the Future Program Grant 96L00102 from the Japan Society for the Promotion of Science.
2 To whom requests for reprints should be addressed, at Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5372; Fax: 81-3-5449-5433; E-mail: yusuke@ims.u-tokyo.ac.jp.
Received 3/ 9/98. Accepted 4/30/98.
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