BRAF and CDC4 mutations in colorectal tumorigenesis

Activating mutations of the BRAF gene have recently been demonstrated in a large fraction of melanomas and a small fraction of other cancers. We have found that BRAF mutations only occur in colorectal cancers lacking KRAS mutations and that BRAF mutation is highly related to mismatch repair status of tumors. Our results provide unambiguous genetic support for the idea that mutations in BRAF and KRAS genes have equivalent effects in tumorigenesis and raise intriguing questions about the types of mutations found in mismatch repair deficient cancers.; An abnormal chromosome number (aneuploidy) is a hallmark of human cancer, recognized for nearly a century. However, the mechanism(s) responsible for aneuploidy has remained elusive. We report the identification of hCDC4/Fbw7/Archipelago mutations in 12% of human colorectal cancers and their precursor lesions. Moreover, we investigated the functional effects of hCDC4 inactivation through targeted disruption of the gene in karyotypically stable colorectal cancer cells. Genetic inactivation of the hCDC4 gene resulted in a striking phenotype associated with micronuclei and chromosomal instability. This instability appeared to be due to a defect in the execution of metaphase and subsequent chromosome transmission. In addition, siRNA experiments in a line derived from normal human epithelial cells suggest that inhibition of hCDC4 can cause chromosomal instability in a cyclin E-dependent manner. In light of these data, we propose that chromosomal instability is caused by specific genetic alterations in a significant fraction of human cancers and can occur prior to malignant conversion.