Somatic mutations of the CDC4 (FBXW7) gene in hereditary colorectal tumors.
OBJECTIVE
Cdc4 (Fbxw7) is a potential tumor suppressor that regulates ubiquitination and proteolysis of multiple targets such as cyclin E, c-Myc, c-Jun and Notch. CDC4 mutations were investigated in 194 colorectal carcinomas and adenomas for comparison between sporadic and hereditary cancers.


METHODS
Mutations of the CDC4 gene were analyzed by PCR-SSCP and sequencing, and loss of heterozygosity (LOH) was analyzed by microsatellite marker analysis.


RESULTS
Somatic CDC4 mutations were detected in 9% (3 of 33) of hereditary nonpolyposis colorectal cancer (HNPCC), 9% (3 of 33) of familial adenomatous polyposis (FAP) carcinomas, and 10% (7 of 73) of sporadic carcinomas. CDC4 mutations were also detected in adenomas at frequencies of 6% (2 of 31) and 4% (1 of 24) in FAP and sporadic cases, respectively. Frameshift mutations were observed in HNPCC tumors, while single-base substitutions predominantly occurred in FAP and sporadic tumors. LOH at the chromosome 4q region was rarely detected in tumors with CDC4 mutations.


CONCLUSIONS
The results indicate that the frequency of CDC4 mutations in colorectal tumors is similar in patients with HNPCC and FAP compared to patients with sporadic carcinomas. Moreover, infrequent LOH suggests that the CDC4 gene does not follow the general 2-hit model.
Hereditary Tumor Research Project, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.
Michiko
M
Miyaki
Tatsuro
T
Yamaguchi
Takeru
T
Iijima
Keiichi
K
Takahashi
Hiroshi
H
Matsumoto
Takeo
T
Mori
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D002874:Chromosome Mapping; D003062:Codon; D015179:Colorectal Neoplasms / Q000378:metabolism*; D004252:DNA Mutational Analysis; D044783:F-Box Proteins / Q000096:biosynthesis*; D000073979:F-Box-WD Repeat-Containing Protein 7; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D009154:Mutation; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis*
D018797:Cell Cycle Proteins; D003062:Codon; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D044767:Ubiquitin-Protein Ligases