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Mutational Analysis of the Transforming Growth Factor ß Receptor Type II Gene in Hereditary Nonpolyposis Colorectal Cancer and Early-onset Colorectal Cancer Patients¹

Korean Hereditary Tumor Registry, Laboratory of Cell Biology, Cancer Research Center, and Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Korea

Somatic mutations in the transforming growth factor ß receptor type II (TGF-ßRII) gene have been observed in various human cancers showing microsatellite instability. Most of the mutations observed were additions or deletions of the mononucleotide repeat sequence present in TGF-ßRII coding region, suggesting that the TGF-ßRII may be a target gene of genomic instability in tumorigenesis. Recently, we reported germ-line frameshift mutations in the mononucleotide repeat sequence of the hMSH6 gene, which is believed to be one of the target genes of genomic instability in tumorigenesis, suggesting the possibility of germ-line mutation in mononucleotide repeat sequences. Moreover, one case of germ-line mutation in the TGF-ßRII gene was identified in a hereditary nonpolyposis colorectal cancer (HNPCC) kindred, indicating the involvement of TGF-ßRII inactivation in tumorigenesis of HNPCC. However, germ-line mutation analysis of all of the coding sequences and the mononucleotide repeat sequence of the TGF-ßRII in HNPCC patients has not yet been fully elucidated. Therefore, to further investigate the presence of germ-line mutations, we screened all of the coding region sequences and mononucleotide repeat sequence of TGF-ßRII from 35 HNPCC, 44 suspected HNPCC, and 45 sporadic early-onset colorectal cancer patients. However, no pathogenic mutations other than silent mutations, introgenic mutation, and polymorphisms were identified. Two silent mutations at codons 309 (ACG to ACA) and 340 (CAT to CAC) in the kinase domain located in exon 4 were detected. A 1-bp cytidine deletion was observed 6 bases from the 3' end of intron. Two polymorphisms were identified at codon 389 (AAC to AAT) and at the fourth-to-last base in intron 3. The polymorphism at codon 389 was more frequent in HNPCC (20%; 7 of 35) and suspected HNPCC patients (18%; 8 of 44) than in nonmalignant control group (10%; 5 of 50). Moreover, the frequency was significantly higher in early-onset colorectal cancer patients (31%; 14 of 45). This is the first report of a different frequency of polymorphism in HNPCC, suspected HNPCC, early-onset colorectal cancer patients, and healthy normal individuals. This result suggests that: (a) germ-line mutation of the TGF-ßRII gene may be a rare event during tumorigenesis in HNPCC and sporadic early-onset colorectal cancer; (b) the mononucleotide repeat sequence of the TGF-ßRII gene is an apparent target of genomic instability but not of germ-line mutation; and (c) the polymorphism of codon 389 (AAC to AAT) is frequent, especially in early-onset colorectal cancer patients, in which it is more frequent than in control group.

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