Abstract
BackgroundThe early to intermediate stages of the majority of colorectal tumours are thought to be driven by aberrations in the Wnt (APC, CTNNB1) and Ras (K-ras) pathways. A smaller proportion of cancers shows mismatch repair deficiency. The aim of this study was to analyse the co-occurrence of these genetic alterations in relation to tumour and patient characteristics.MethodsIn a group of 656 unselected sporadic colorectal cancer patients, aberrations in the APC, K-ras, CTNNB1 genes, and expression of hMLH1 were investigated. Additionally, tumours were divided in groups based on molecular features and compared with respect to patient's age at diagnosis, sex, family history of colorectal cancer, tumour sub-localisation, Dukes' stage and differentiation.ResultsMutations at the phosphorylation sites (codons 31, 33, 37, and 45) in the CTNNB1 gene were observed in tumours from only 5/464 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.ConclusionCTNNB1 mutations seem to be of minor importance in sporadic colorectal cancer. The main differences in tumour and patient characteristics are found between groups of patients based on mismatch repair deficiency.
Highlights
The early to intermediate stages of the majority of colorectal tumours are thought to be driven by aberrations in the Wnt (APC, CTNNB1) and Ras (K-ras) pathways
A recent study based on the analysis of APC, K-ras and TP53 genes concluded that simultaneous occurrence of all three genetic alterations is rare and that multiple genetic pathways may be relevant to colorectal cancer [9]
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 who harboured a tumour with an APC and/or K-ras mutation
Summary
The early to intermediate stages of the majority of colorectal tumours are thought to be driven by aberrations in the Wnt (APC, CTNNB1) and Ras (K-ras) pathways. Carcinogenesis is a multi-step process that involves the accumulation of numerous genetic and epigenetic changes in cells [1]. These genetic aberrations affect a limited number of identified pathways that are involved in (colorectal) carcinogenesis [2]. In tumours lacking these APC mutations [7], activating missense mutations at one of the phosphorylation sites at codons 31, 33, 37 and 45 of exon 3 of the CTNNB1 gene (encoding the β-catenin protein) can render it stable as it can no longer be tagged for cellular degradation. Activation of the Ras pathway in cancer is marked by the loss of the intrinsic GTPase activity of the Ras protein, which can be ascribed to missense mutations in codons 12 and 13 of exon 1, which are responsible for 90% activating mutations in the of the K-ras gene [8]
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