MLH1, BRAF and p53 - searching for significant markers to predict evolution towards adenocarcinoma in colonic sessile serrated lesions

Rom J Morphol Embryol. 2021 Oct-Dec;62(4):971-979. doi: 10.47162/RJME.62.4.09.


Background and aim: Colonic serrated lesions are premalignant lesions, using an alternative malignization pathway, including multiple genetic and epigenetic alterations, as: mismatch repair deficiency due to MutL homolog 1 (MLH1) promoter methylation, tumor protein p53 (TP53) mutations, activating mutations of v-Raf murine sarcoma viral oncogene homolog B (BRAF) and Kirsten rat sarcoma viral oncogene homolog (KRAS). Our study aims to evaluate MLH1, BRAF and p53 immunohistochemical (IHC) status in sessile serrated lesions (SSLs), with and without dysplasia.

Materials and methods: This is a retrospective case-control study including 20 SSLs with dysplasia and 20 SSLs without dysplasia (matching sex and age). IHC expression of MLH1, BRAF and p53 was evaluated as the percent of nuclear loss of MLH1, cytoplasmic positivity of BRAF and nuclear positivity of p53. Data concerning age, sex, localization of the lesion, dysplasia and IHC results were statistically processed using Microsoft Excel.

Results: We had very polymorphous patterns of IHC expression for BRAF, MLH1 and p53, especially in the dysplastic group. Thus, two patients were BRAF+∕MLH1-∕p53+, three were BRAF+∕MLH1-∕p53-, one was BRAF+∕MLH1+∕p53- and six were BRAF+∕MLH1+∕p53+. Dysplastic lesions without BRAF mutation exhibited the following phenotype: one case BRAF-∕MLH1-∕p53+, four BRAF-∕MLH1-∕p53- and three BRAF-∕MLH1+∕p53+. In the control group (SSLs without dysplasia), there was a more homogenous distribution of cases: eight cases BRAF+∕MLH1+∕p53-, seven BRAF-∕MLH1+∕p53-, one BRAF-∕MLH1-∕p53+, two BRAF-∕MLH1-∕p53- and two BRAF-∕MLH1+∕p53+.

Conclusions: There are more routes on the serrated pathway, with different mutations and time of acquisition of each genetic or epigenetic lesion with the same morphological result. These lesions should be stratified according to their risk to poor outcome and their need to further surveillance.

MeSH terms

  • Adenocarcinoma* / pathology
  • Adenoma* / pathology
  • Animals
  • Case-Control Studies
  • Colonic Polyps* / pathology
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / pathology
  • Humans
  • Hyperplasia
  • Mice
  • MutL Protein Homolog 1 / genetics
  • Mutation / genetics
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Retrospective Studies
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*


  • MLH1 protein, human
  • Mlh1 protein, mouse
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MutL Protein Homolog 1
  • Proto-Oncogene Proteins p21(ras)