Abstract
BackgroundColorectal (CRC) carcinogenesis through various morphological stages has been linked to several genetic and epigenetic changes. The Raf/MEK/ERK (MAPK) signal transduction cascade is an important mediator of a number of cellular fates.MethodsIn this study, we investigated the presence of B-raf and K-ras mutations in 94 consecutive cases of primary colon adenocarcinoma in correlation with the immunohistochemical expression of total and activated ERK and the expression of mismatch repair proteins (MMR) hMLH1 and hMSH2 as well as their correlations with standard clinicopathological parameters.ResultsThe immunostaining pattern for total and activated ERK was nuclear and cytoplasmic. hMLH1 and hMSH2 proteins were preserved in 45/63 (71.43%) cases and 35/53 (66.04%) cases respectively. Total ERK nuclear expression, was positively correlated with tumor stage (p = 0.049), whereas nuclear pERK expression was positively correlated with histological grade (p = 0.0113) and tumor stage (p = 0.0952), although the latter relationship was of marginal significance. DNA sequencing showed that 12 samples (12.7%) had a mutation in B-RAF Exon 15 and none in Exon 11, whereas 22 (23.4%) had a K-ras mutation. Disruption of the MAP kinase pathway-either through K-ras or B-raf mutation-was detected in 37% of all the examined cases, although the overexpression of total and activated ERK1/2 was not correlated with the mutational status of K-ras or B-raf genes. Finally, the preservation of hMLH1 or hMSH2 immunoexpression was not correlated with the presence of B-raf and/or K-ras mutations.ConclusionsIn this study, we present evidence that ERK activation occurs in a K-ras or B-raf -independent manner in the majority of primary colon cancer cases. Moreover, B-raf mutations are not associated with mismatch-repair deficiency through loss of hMLH1 or hMSH2 expression. Activated ERK could possibly be implicated in tumor invasiveness as well as in the acquisition of a more aggressive phenotype.
Highlights
Colorectal (CRC) carcinogenesis through various morphological stages has been linked to several genetic and epigenetic changes
Associations between ERK, pERK, hMLH1 and hMSH2 expression levels with B-RAF and/or K-RAS mutational status The results of molecular analysis are shown in Additional file 1
The presence of either B-raf or K-ras mutation was marginally associated with the presence of cytoplasmic ERK expression (Fisher’s exact test, p = 0.097), suggesting that the proportion of cytoplasmic ERK positivity is marginally higher in the mutated cases when compared to the unmutated ones
Summary
Colorectal (CRC) carcinogenesis through various morphological stages has been linked to several genetic and epigenetic changes. In addition to CIN and MSI pathways, a third pathway, the epigenetic instability, which is thought to be largely driven by hypermethylation-induced silencing of tumor suppressor-like genes, has been implicated in the progression of colorectal carcinogenesis [4]. According to this notion, contemporary literature suggests that CRC in general develops through two independent pathways that involve sequences of genetic and epigenetic alterations associated with pathological and clinical features: the adenoma pathway in 70-80% and the newly recognized, the serrated pathway in the remaining 20-30% [5]. The somatic molecular features which characterize the newly introduced serrated pathway to CRC include activating mutations in B-raf [6] and widespread hypermethylation of gene promoters (CIMP) [7] with or without MSI [6]
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