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Mutations of p16^Ink4/CDKN2 and p15^Ink4B/MTS2 Genes in Biliary Tract Cancers¹

Department of Biochemistry and Molecular Oncology, Institute of Basic Medical Sciences [S. Y., Y. I., H. S., S. H., M. H., M. M., K. U.] and Department of Surgery, Institute of Clinical Medicine [S. Y., T. T., K. F.], University of Tsukuba, Tsukuba 305, Japan

p16^Ink4 and p15^Ink4B are cyclin-dependent kinase 4 inhibitors and link to the regulation of cell cycle in mammalian cells. The genes encoding these inhibitors are located at 9p21, which is a frequent site of allelic loss in various types of tumors. Twenty-five primary biliary tract cancers were examined for somatic mutations in p16^Ink4/CDKN2, p15^Ink4B/MTS2, p53, and K-ras genes and allelic loss of 9p21 by microsatellite analysis. Four biliary tract cancer cell lines were analyzed for homozygous deletions and point mutations. We found frequent homozygous deletions in p16^Ink4/CDKN2 and p15^Ink4B/MTS2 genes in the biliary tract cancer cell lines. Each cancer cell line had alteration of either p16^Ink4/CDKN2, p15^Ink4B/MTS2, or p53 genes. In primary tumors, 16 of 25 (64%) biliary tract cancers had point mutations in the p16^Ink4/CDKN2 gene. These include 14 missense and 2 silent mutations. The frequency of mutations in gall bladder cancer and hilar bile duct cancer were 80% (8 of 10) and 63% (5 of 8), respectively. Each of codons 1, 80, and 111 was changed in two cases of these cancers. One of three intrahepatic bile duct cancers, one of two common bile duct cancers, and one of two ampullary cancers had mutations in the p16^Ink4/CDKN2 gene. In contrast, no mutation in the p15^Ink4B/MTS2 gene, one base change in the K-ras gene, and one loss of heterozygosity at the IFN locus in 25 cancers and one base change in the p53 gene in 19 cancers were observed. These results suggest that p16^Ink4/CDKN2, rather than p15^Ink4B/MTS2 or p53 genes, and its inactivation may be important in biliary tract carcinogenesis.

¹ This study was supported in part by Grants-in-Aid for Scientific Research (06280104) and Cancer Research (07255201) from the Ministry of Education, Science and Culture, for 2nd term of Comprehensive 10-year Strategy for Cancer Control, and for Cancer Research (5-5) from the Ministry of Health and Welfare of Japan.

² To whom requests for reprints should be addressed, at the Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305, Japan.

Received 1/17/95. Accepted 5/19/95.

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