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The homeobox gene MEIS1 is methylated in BRAF (p.V600E) mutated colon tumors

Ashwin A Dihal1, Arnoud Boot, Eddy H van Roon

  • 1Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Plos One
|November 19, 2013
PubMed

Insights

Right-sided colorectal cancer (CRC) with BRAF (p.V600E) mutations frequently shows MEIS1 gene promoter methylation. This epigenetic change is linked to reduced MEIS1 gene expression, impacting tumor development.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Colorectal cancer (CRC) development involves gene mutations and epigenetic alterations like DNA methylation.
  • Right-sided colon tumors often exhibit BRAF (p.V600E) mutations and higher methylation grades compared to left-sided tumors.
  • Site-specific DNA methylation in CRC influences the expression of genes associated with tumorigenesis.

Purpose of the Study:

  • To identify DNA methylation changes specifically associated with the BRAF (p.V600E) mutation status in colorectal cancer.
  • To investigate the relationship between BRAF (p.V600E) mutation and MEIS1 gene methylation and expression.

Main Methods:

  • DNA methylation profiling of colon tumor and paired healthy tissue using macro-dissection.
  • Single gene analysis to compare methylation between BRAF (p.V600E) and BRAF wild-type tumors.
  • Validation of findings using methylation-specific PCR and an independent patient cohort (n=228).

Main Results:

  • MEIS1 was identified as the most significantly differentially methylated gene in BRAF (p.V600E) tumors.
  • BRAF (p.V600E) mutation was strongly associated with MEIS1 methylation (OR: 13.0, P<0.0001) in an independent cohort.
  • MEIS1 promoter methylation correlated with decreased MEIS1 and MEIS1 D27 gene expression in tumor samples and cell lines.

Conclusions:

  • BRAF (p.V600E) positive colon tumors exhibit significant MEIS1 promoter methylation.
  • This methylation is associated with reduced expression of MEIS1 and its truncated form, MEIS1 D27.
  • MEIS1 methylation originates in both epithelial and stromal fractions of BRAF (p.V600E) tumors.

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