In colorectal cancer, the molecular alterations that lead to metastasis are not clearly established, probably because of their high genetic complexity. To identify combinations of genetic changes involved in tumor progression and metastasis, we focused on chromosome instable (CIN) colon cancers. We compared by allelotyping of 33 microsatellites, the genomic alterations of 38 primary colon tumors with the synchronously resected matched liver metastases (CLM). We observed that (i) the number of patients with alterations at certain loci did not differ significantly between the whole primary tumor and the paired CLM, (ii) a group of patients had fewer alterations in the metastasis when compared with the matched primary tumor. A 2-way hierarchical unsupervised clustering of the allelotyping data revealed 2 tumor subtypes that have different levels of CIN (CIN-High, CIN-Low). Both subtypes have a minimal common set of alterations at chromosomes 8p, 17p and 18q, but does not include alteration at 5q or mutation at K-Ras. These 2 subtypes were also observed using a collection of 104 independent primary CIN colon tumors. In addition, we found a third subtype, consisting of tumors with a very low number of alterations not associated with specific loci (CIN-Very Low). We found that colon carcinogenesis may require a minimal set of alterations and that, in contrast to the current hypothesis, the level of CIN does not correlate with tumor progression. Therefore, our results suggest that metastasis potential could be present at very early stages of tumor development. ' 2006 Wiley-Liss, Inc.Key words: allelotyping; colon cancer; chromosome instability; metastasis; matched samples Colorectal carcinoma (CRC) is the second leading cause of cancer in the Western world, and death is usually related to liver metastases. Numerous molecular and cytogenetic studies have strengthened the hypothesis that the development of CRC involves stepwise accumulation of defective tumor suppressor genes and of oncogenes especially APC, K-RAS and p53 genes with loss of 18q.1-6 However, there is now evidence that CRC arises from alterations in 2 distinct pathways, either from alterations of DNA mismatch repair resulting in microsatellite instability (MIN) 7,8 or, for 80% of CRC, from genomic instabilities described as chromosome instability (CIN), leading to loss of heterozygosity (CIN).9 Open interesting questions include the existence of various genetic origins for CIN colorectal cancers linked either to their localization or to the initial hit like APC, RAS or other still unknown molecular defects affecting the genome stability.
10Current pathological or molecular markers poorly predict individual prognosis or response to treatment. This failure could be linked to genetic tumor complexity and intertumor heterogeneity, and to the contexts of colorectal tumor collections, which frequently include all stages and/or tumor locations as well as rectal tumors.11-14 Gene expression profiling data appear to be even more confusing, with only few genes show...