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[Cancer Research 58, 1021-1026, March 1, 1998]
© 1998 American Association for Cancer Research

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Activation of the ß-Catenin Gene by Interstitial Deletions Involving Exon 3 in Primary Colorectal Carcinomas without Adenomatous Polyposis Coli Mutations1

Kyoko Iwao, Syoji Nakamori2, Masao Kameyama, Shingi Imaoka, Moritoshi Kinoshita, Takafumi Fukui, Shingo Ishiguro, Yusuke Nakamura3 and Yasuo Miyoshi

Division of Clinical Genetics, Department of Medical Genetics, Biomedical Research Center, Osaka University Medical School, Suita City, Osaka 565 [K. I., Y. N., Y. M.]; Departments of Surgery [S. N., M. K., S. Im.] and Pathology [S. Is.], Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka City, Osaka 537; Otsuka Assay Laboratory, Otsuka Pharmaceutical Co. Ltd., Kawauchi Cho, Tokushima City, Tokushima 771-01 [M. K., T. F.]; and Laboratory of Molecular Medicine, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108 [Y. N.], Japan

Among 222 primary colorectal cancers we examined, 58 showed no detectable APC mutations by the protein truncation test. We screened those 58 tumors for somatic mutations in the ß-catenin gene. Although amino acid substitutions in serine or threonine residues in exon 3 had been reported, we found no such mutations; however, in seven tumors, we detected somatic interstitial deletions of 234–760 bp, each of which included all or part of exon 3. Short nucleotide sequences at both ends of each deletion were either identical or complementary, indicating that repeated or inversely repeated sequences were involved in the somatic rearrangements. Reverse transcription-PCR experiments using RNAs isolated from three of these seven tumors detected transcripts that lacked exon 3, in addition to the normal transcript. In one of these cases, we confirmed accumulation of aberrant ß-catenin protein in cytoplasm and nuclei of cancer cells by Western and immunohistochemical analyses. This result suggested that, in the absence of a peptide encoded by exon 3, ß-catenin is stabilized and has a dominant oncogenic effect on colorectal tumorigenesis.

1 This work was supported in part by a special grant for Strategic Advanced Research on Cancer from the Ministry of Education, Science, Sports and Culture of Japan, and Research for the Future Program Grant 96L00102 from the Japan Society for the Promotion of Science.

2 Present address: Second Department of Surgery, Osaka University Medical School, 2-2 Yamadaoka, Suita City, Osaka 565, Japan.

3 To whom requests for reprints should be addressed. Phone: 81-3-5449-5372; Fax: 81-3-5449-5433; E-mail: yusuke@ims.u-tokyo.ac.jp.

Received 9/22/97. Accepted 1/ 6/98.




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