Colorectal cancer genomics: evidence for multiple genotypes which influence survival.

Colorectal cancer (CRC) is a leading cause of cancer death and the mechanism for variable outcome in this disease is not yet fully understood. It is hypothesized that differences in the genetic make-up of tumours may be partially responsible for the differences observed in survival among same staged individuals for this disease. In this study the tumour genomes of 29 consecutive patients undergoing surgery for Dukes' C CRC were assessed by comparative genomic hybridization (CGH). In addition, the CGH profiles from the tumours were compared with those from eight colorectal cell lines. Great variation in genetic grade (all detectable aberrations i.e., loss + gain) was observed in 29 Dukes' C colorectal tumours by CGH (median four aberrations per tumour, range 0-20). Gain was found in 76% and loss in 41% of tumours. The most frequently observed regions of gain were 13q (27.6%), 20q (27.6%), 7p (24.1%), 8q (24.1%), and 1q (20.7%) and loss were 18q (31%), 4q (20.7%), 17p (20.7%), 18p (20.7%), and 15q (20.1%). None of these specific genomic aberrations were associated with patient survival. However, patients with more than two aberrations had a better survival than patients with fewer regions of loss and gain (P = 0.02). CRC cell lines had similar regions of loss or gain as the tumours. However, the frequency of genomic aberrations was much greater in the CRC cell lines. Although genomic change in CRC is relevant to the survival of patients with Dukes' C CRC, careful analysis is required to identify cell lines which are representative models of CRC genomics.

Characterization of the topoisomerase I locus in human colorectal cancer.

DNA topoisomerase I (topo I) is the principle target for Camptothecin and its analogues. The topo I gene is located on chromosome 20q11.2-q13.1 and variation in topo I gene copy number has been shown to have impact on the in vitro sensitivity to topoisomerase I inhibitor chemotherapy. Fluorescence in situ hybridization (FISH) was used to detect and compare the TOPO I gene copy number between metaphase and interphase nuclei in a panel of 7 colorectal cancer cell lines. TOPO I gene copy number varied from 2 to 8 between cell lines, and signal in interphase nuclei demonstrated a linear relationship with that detected in metaphase nuclei. The structure of gene amplification included isochromosome formation, amplicon extension, and marker chromosome generation. Comparative genomic hybridization (CGH) was then used to further define the region of gain on chromosome 20. The region of gain contained the topo I gene and involved nearly all of 20q in most cases. This demonstrates a high degree of intrinsic variation in topo I gene copy number and the involvement of a 20q amplicon in colorectal cancer, which may have important implications for colorectal tumorigenesis and the use of chemotherapy.