title: ERK/pERK expression and B-raf mutations in colon adenocarcinomas: correlation with clinicopathological characteristics.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology, National and Kapodistrian University of Athens, Medical School, 75 Mikras Asias street, Greece. glevidou@yahoo.gr
authors.forename: Georgia
authors.initials: G
authors.lastname: Levidou
authors.forename: Angelica A
authors.initials: AA
authors.lastname: Saetta
authors.forename: Fanie
authors.initials: F
authors.lastname: Gigelou
authors.forename: Maria
authors.initials: M
authors.lastname: Karlou
authors.forename: Polyanthi
authors.initials: P
authors.lastname: Papanastasiou
authors.forename: Angeliki
authors.initials: A
authors.lastname: Stamatelli
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Kavantzas
authors.forename: Nikolaos V
authors.initials: NV
authors.lastname: Michalopoulos
authors.forename: George
authors.initials: G
authors.lastname: Agrogiannis
authors.forename: Efstratios
authors.initials: E
authors.lastname: Patsouris
authors.forename: Penelope
authors.initials: P
authors.lastname: Korkolopoulou
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000074081:MutS Homolog 3 Protein; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D018631:ras Proteins / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C117307:KRAS protein, human; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins