The detailed characterization of human colon cancer stem cell lines already has revealed that they have several copy number changes in their genome, which apparently increase in number with prolonged culturing time.
Extensive results have also been obtained for the development of genomic and transcriptomic changes in various mouse models. We have managed to obtain detailed maps about genomic changes and transcriptional data from a series ranging from very early changes to progressive tumours. This provided us with first insights into forms of instability occurring during tumour initiation and during progression. Furthermore, Partners 4 and 6 have succeeded in developing novel mouse models capable of replicating human disease with high fidelity.
The consortium has observed significant differences in telomere lengths between cases and controls and between patients who have/have not been exposed to chemotherapy (486% shortening of telomere length). This suggests that telomere length even in tissue not involved in tumourigenesis may have a significant impact on disease susceptibility.
Regarding underlying mechanisms of genomic instability we were able to demonstrate that the deletion of p53 (a protein normally inhibiting tumour growth) leads to survival of telomere dysfunctional stem cells in mice. The survival of these instable stem cells leads to chromosomal instability and accelerated tissue atrophy and intestinal failure.
Sophisticated bioinformatic approaches have been developed and are currently in use. For example, a particularly useful tool is “ClueGo”, developed by Beneficiary 8, which facilitates the identification of pathways whose function may be compromised by changes in the genome. Thus the GENINCA-consortium was able to identify pathways involved during colorectal tumorigenesis and the specific correlation with immunologic response data.