Mutations in APC, CTNNB1 and K-ras genes and expression of hMLH1 in sporadic colorectal carcinomas from the Netherlands Cohort Study.

PG - 160 AB - BACKGROUND: In colorectal carcinogenesis several pathways have been identified. The majority of colorectal tumours are thought to be driven by a sequential accumulation of mutations in the APC, K-ras and TP53 genes. A smaller proportion of cancers displays microsatellite instability. METHODS: In a group of 656 unselected incident colorectal cancer patients, the occurrence of mutations in the APC, K-ras, and CTNNB1 genes as well as expression of hMLH1 was investigated. Additionally, tumours were divided in groups on the basis of molecular features and compared with respect to age at diagnosis, sex, family history of colorectal cancer, tumour sub-localisation, Dukes' stage and tumour differentiation. RESULTS: Mutations at the phosphorylation sites in the CTNNB1 gene were observed in tumours from only five of 464 patients. Tumours with truncating APC mutations and activating K-ras mutations in codons 12 and 13 occurred at similar frequencies (37% (245/656) and 36% (235/656), respectively). Seventeen percent of tumours harboured both an APC and a K-ras mutation (109/656). Nine percent of all tumours (58/656) lacked hMLH1 expression. Patients harbouring a tumour with absent hMLH1 expression were older, more often women, more often had proximal colon tumours that showed poorer differentiation when compared to patients harbouring tumours with an APC and/or K-ras mutation. CONCLUSIONS: From data of a large, unselected group of sporadic colorectal cancer patients, we conclude that several pathways in colorectal cancer can be identified, but that the main differences in tumour and patient characteristics are found between groups of patients based on mismatch repair deficiency