The online version of this article (doi:10.1186/1477-7819-10-47) contains supplementary material, which is available to authorized users.
Georgia Levidou, Angelica A Saetta contributed equally to this work.
The authors declare that they have no competing interests.
The manuscript was edited by GL, AAS Immunohistochemical staining was performed by PP and evaluated by GL, PK and NK. Molecular analysis was organized by AAS and performed by FG, MK and AS. Genomic DNA isolation was performed by MK. Statistical analysis was done by GL (MSc in Biostatistics). Clinical data of the patients were collected by NVM. The respective literature was collected by GA. The supervision and organization of the research program was performed by EP and PK. All the authors have read and approved the final manuscript.
Colorectal (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.
In 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.
The 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.
In 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.
Additional file 1: Supplementary table presenting all samples with their clinical information and the staining results. This a comprehensive table in which all samples of the present study are listed along with their clinical information (i.e. age, gender) and the staining results of the examined proteins. (DOC 204 KB)12957_2011_976_MOESM1_ESM.DOC
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World Health Organization Fact Sheet No 297, October 2011 (Accessed December 2011)
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- ERK/pERK expression and B-raf mutations in colon adenocarcinomas: correlation with clinicopathological characteristics
Angelica A Saetta
Nikolaos V Michalopoulos
- BioMed Central
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