Array-CGH analysis of microsatellite-stable, near-diploid bowel cancers and comparison with other types of colorectal carcinoma

Abstract

Microsatellite-stable, near-diploid (MSI−CIN−) colorectal carcinomas have been reported, but it is not clear as to whether these tumours form a discrete group or represent one end of the distribution of MSI−CIN+ cancers. In order to address this question, we screened 23 MSI−CIN− colorectal cancers for gains and losses using array-based comparative genomic hybridization (aCGH) based on large-insert clones at about 1 Mb density. We compared our findings with those from a small set of MSI+CIN+ cancers, and with our reported data from MSI−CIN+ and MSI+CIN− cancers. We found no evidence of any form of genomic instability in MSI−CIN− cancers. At the level of the chromosome arm, the MSI−CIN− cancers had significantly fewer gains and losses than MSI−CIN+ tumours, but more than the MSI+CIN− and MSI+CIN+ lesions. The chromosomal-scale changes found in MSI−CIN− cancers generally involved the same sites as those in MSI−CIN+ tumours, and in both cancer groups, the best predictor of a specific change was the total number of such changes in that tumour. A few chromosomal-scale changes did, however, differ between the MSI−CIN− and MSI−CIN+ pathways. MSI−CIN− cancers showed: low frequencies of gain of 9p and 19p; infrequent loss of 5q and a high frequency of 20p gain. Overall, our data suggested that the MSI−CIN− group is heterogeneous, one type of MSI−CIN− cancer having few (⩽6) chromosomal-scale changes and the other with more (⩾10) changes resembling MSI−CIN+ cancers. At the level of individual clones, frequent and/or discrete gains or losses were generally located within regions of chromosomal-scale changes in both MSI−CIN− and MSI−CIN+ cancers, and fewer losses and gains were present in MSI−CIN− than MSI−CIN+ tumours. No changes by clone, which were specific to the MSI−CIN− cancers, were found. In addition to indicating differences among the cancer groups, our results also detected over 50 sites (amplifications, potential homozygous deletion and gains or losses which extended over only a few megabases) which might harbour uncharacterized oncogenes or tumour suppressor loci. In conclusion, our data support the suggestion that some MSI−CIN− carcinomas form a qualitatively different group from the other cancer types, and also suggest that the MSI−CIN− group is itself heterogeneous.