High copy amplification of the Aurora-A gene is associated with chromosomal instability phenotype in human colorectal cancers.
Chromosomal instability (CIN) is a common but not universal feature of colorectal cancer (CRC); however, the molecular basis for CIN is controversial and poorly understood. There are many plausible mechanisms proposed for CIN, including disruption of G1/S and G2/M checkpoint regulation, and alterations in the spindle checkpoint genes. However, mutations in individual growth regulatory genes are not commonly observed in CRC. Therefore, a more comprehensive analysis of the genes involved in each cell cycle checkpoint regulatory pathway might be required to evaluate a possible role for involvement in CIN. We investigated the presence of high copy amplification of the cyclin E, Aurora-A, Skp2 genes, mutation of ubiquitin ligase CDC4, and promoter methylation of Mad2L1, as well as the expression of the gene products in a panel of 11 human CRC cell lines as well as 48 human CRC specimens. In the cell lines with CIN, we found amplification of the Aurora-A, cyclin E and Skp2 genes, and a mutation in the CDC4 gene, all of which resulted in altered expression of the cognate proteins. In the human CRC tissues, amplification of Aurora-A was frequent (29%), while alterations were rarely observed in cyclin E, Skp2 or CDC4. Aurora-A amplification was strongly associated with a high fractional allelic loss score (p = 0.0001), but not with microsatellite instability, nor with the promoter methylation phenotype in these tumors. Our data confirm involvement in the CDC4-cyclin E pathway of the development of the CIN phenotype in human CRC, and find that amplification of the Aurora-A is a common target for disruption of this pathway.
Nishida
Naoshi
N
Department of Internal Medicine, Division of Gastroenterology, Charles A. Sammons Caner Center, Baylor University Medical Center, Dallas, Texas 75246, USA.
Nagasaka
Takeshi
T
Kashiwagi
Kazuhiro
K
Boland
C Richard
CR
Goel
Ajay
A
D000368:Aged; D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D015179:Colorectal Neoplasms / Q000235:genetics*; D019927:Cyclin E / Q000235:genetics; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D005784:Gene Amplification; D006801:Humans; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D018797:Cell Cycle Proteins; D019927:Cyclin E; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D044786:S-Phase Kinase-Associated Proteins; D044767:Ubiquitin-Protein Ligases; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases