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A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer
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Published on: July 6, 2017

Somatic mutations of the CDC4 (FBXW7) gene in hereditary colorectal tumors

Michiko Miyaki1, Tatsuro Yamaguchi, Takeru Iijima

  • 1Hereditary Tumor Research Project, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.

Oncology
|May 8, 2009
PubMed
Abstract

Insights

CDC4 (Fbxw7) mutations are similarly frequent in hereditary and sporadic colorectal cancers. Infrequent loss of heterozygosity suggests CDC4 does not follow the typical two-hit tumor suppressor model.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cdc4 (Fbxw7) functions as a tumor suppressor by regulating the ubiquitination and degradation of key proteins like cyclin E, c-Myc, c-Jun, and Notch.
  • Investigating CDC4 mutations is crucial for understanding colorectal cancer development, particularly in distinguishing between sporadic and hereditary forms.

Purpose of the Study:

  • To compare the frequency and types of CDC4 gene mutations in colorectal carcinomas and adenomas between sporadic and hereditary cancer cases.
  • To assess the role of loss of heterozygosity (LOH) at the 4q region in tumors with CDC4 mutations.

Main Methods:

  • Mutation analysis of the CDC4 gene was performed using Polymerase Chain Reaction-Single Strand Conformation Polymorphism (PCR-SSCP) and sequencing.
  • Loss of heterozygosity (LOH) was analyzed using microsatellite marker analysis.

Main Results:

  • Somatic CDC4 mutations were found in 9% of hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP) carcinomas, and 10% of sporadic carcinomas.
  • Mutations were also detected in adenomas (6% FAP, 4% sporadic). Frameshift mutations were noted in HNPCC, while single-base substitutions predominated in FAP and sporadic tumors.
  • Loss of heterozygosity (LOH) in the chromosome 4q region was infrequent in tumors harboring CDC4 mutations.

Conclusions:

  • The frequency of CDC4 mutations in colorectal tumors is comparable across HNPCC, FAP, and sporadic cancer types.
  • The low incidence of LOH suggests that the CDC4 gene may not operate under the conventional two-hit hypothesis for tumor suppression.

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