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Development and Applications of a ß-Catenin Oligonucleotide Microarray

ß-Catenin Mutations Are Dominantly Found in the Proximal Colon Cancers with Microsatellite Instability¹

Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi 411-764, Korea [S. Y. P., S-Y. J., H. K. K., J-G. P.], and Korean Hereditary Tumor Registry, Laboratory of Cell Biology, Cancer Research Center and Cancer Research Institute [I-J. K., H. C. K., J-H. P., Y. S., J-L. K., J-G. P.] and Department of Surgery [S-B. L., J-G. P.], Seoul National University College of Medicine, Seoul, Korea

ß-catenin mutations have been identified in a variety of human malignancies; most of these are missense mutations restricted at hot-spot areas in exon 3. ß-catenin mutations are known to be highly associated with colorectal cancers with microsatellite instability (MSI). More than 70 ß-catenin mutations have been reported in colorectal cancers, and 90% of ß-catenin mutations have been found in 11 codons (codons 29, 31, 32, 33, 34, 35, 37, 38, 41, 45, and 48) as missense mutations or in-frame deletions. We have developed an oligonucleotide microarray for detecting ß-catenin mutations at these 11 codons. The developed oligonucleotide microarray can detect a total of 110 types of ß-catenin mutations, including the 60 mutations reported previously. Nine ß-catenin mutations were identified in this study by five different methods, i.e., PCR- single-strand conformational polymorphism, denaturing high performance liquid chromatography, direct sequencing, cloning-sequencing, and with an oligonucleotide microarray. All nine of the mutations were identified by denaturing high performance liquid chromatography, cloning-sequencing, and by the oligonucleotide microarray. However, PCR-single-strand conformational polymorphism missed 1 ß-catenin mutation and direct sequencing missed 2. Five ß-catenin mutations from 74 colorectal carcinomas (34 proximal colon cancers and 40 distal colorectal cancers) and 4 ß-catenin mutations from 31 colorectal cancer cell lines (7 from the proximal colon, 6 from the distal colorectum, and 18 unknown) were identified. In colorectal carcinomas, all 5 of the ß-catenin mutations were found in proximal colon tumors. In colorectal cancer cell lines, 2 of 4 cell lines with ß-catenin mutations originated from the proximal colon, and the remaining 2 cell lines were simply described as having originated from the colon. Considering the relationships among ß-catenin mutations, MSI, and tumor location, the frequency of ß-catenin mutations was found to be meaningfully higher in colorectal carcinomas with MSI than in those with microsatellite stability (P < 0.001); moreover, MSI was found to be more frequent in proximal colon tumors (P < 0.01). In addition, ß-catenin mutations were also found to be associated with proximal colon cancer (P = 0.017).

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