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Letters to Nature

Nature 428, 77-81 (4 March 2004) | doi:10.1038/nature02313; Received 17 September 2003; Accepted 5 January 2004

Inactivation of hCDC4 can cause chromosomal instability

Harith Rajagopalan1, Prasad V. Jallepalli1,2, Carlo Rago1, Victor E. Velculescu1, Kenneth W. Kinzler1, Bert Vogelstein1,3 & Christoph Lengauer1

  1. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
  2. Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
  3. Howard Hughes Medical Institute, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21231, USA

Correspondence to: Christoph Lengauer1 Email: lengauer@jhmi.edu

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Aneuploidy, an abnormal chromosome number, has been recognized as a hallmark of human cancer for nearly a century1; however, the mechanisms responsible for this abnormality have remained elusive. Here we report the identification of mutations in hCDC4 (also known as Fbw7 or Archipelago) in both human colorectal cancers and their precursor lesions. We show that genetic inactivation of hCDC4, by means of targeted disruption of the gene in karyotypically stable colorectal cancer cells, results in a striking phenotype associated with micronuclei and chromosomal instability. This phenotype can be traced to a defect in the execution of metaphase and subsequent transmission of chromosomes, and is dependent on cyclin E—a protein that is regulated by hCDC4 (refs 2–4). Our data suggest that chromosomal instability is caused by specific genetic alterations in a large fraction of human cancers and can occur before malignant conversion.