Genetic pathways in the evolution of morphologically distinct colorectal neoplasms

Colorectal adenomas can be morphologically classified as exophytic or flat. Polypoid cancers and cancers arising de novo (i.e., without any adenomatou s component) might be the results of genetic progression from exophytic and flat adenomas, respectively. In this study, we examined 94 morphologically distinct neoplastic specimens for mutations in K-RAS and analyzed 10 micro satellite loci tightly linked to the tumor suppressor genes APC, p53, DCC/S MAD4, hMSH2, and hMLH1. K-RAS mutations were significantly associated with exophytic adenomas [11 of 21 (52%)] compared to flat adenomas [2 of 13 (15% ), P < 0.03] and polypoid cancers [17 of 25 (68%)] compared to cancers aris ing de novo [7 of 25 (28%), P < 0.01]. Two polypoid cancer cases demonstrat ed three and four different K-RAS mutations, respectively, suggesting multi ple areas of clonal expansion. Cancers arising de novo mere significantly a ssociated with loss of heterozygosity (LOH) at chromosome 3p compared to po lypoid cancers [6 of 18 (33%) versus 1 of 20 (5%), P < 0.03], whereas the p revalence of LOH at chromosomes 2p, 59, 17p, and 18q and microsatellite ins tability were not different between the groups. For all cancers, LOH at chr omosomes 17p and 18q occurred in 47 and 51%, respectively. However, LOH at 17p and 18q occurred in 0 and 16% of benign lesions, respectively, suggesti ng their role in malignant transformation. There was no difference in LOH a t chromosomes 17p and 18q between exophytic and flat lesions. These finding s suggest that (a) mutant K-RAS is associated with the exophytic growth of colonic neoplasms, and that (b) some colorectal cancers arising de novo los e chromosome 3p during their evolution, which is not seen in polypoid cance rs. Half of all cancers lose chromosomes 17p and 18q at or near the maligna nt transition of benign lesions as reported previously, irrespective of mor phology. There may be more than one genetic avenue for colorectal cancer fo rmation, and this correlates with the morphological characteristics.