title: Methylation changes in the TFAP2E promoter region are associated with BRAF mutation and poorer overall & disease free survival in colorectal cancer.
abstract: BACKGROUND
  BRAF mutant colorectal cancer carries a poor prognosis which is thought to be related to poor response to conventional chemotherapy. BRAF mutation is associated with the serrated tumour phenotype. We hypothesised that one of the mechanisms by which BRAF mutant colorectal cancer demonstrate poor outcomes with chemotherapy is abnormal gene methylation.
  
  
  METHODS
  The Cancer Genome Atlas (TCGA) methylation data was analysed using a linear regression model with BRAF mutation as an independent variable. Expression datasets were also obtained to correlate functional changes. Top differentially methylated probes were taken forward for validation by methylation pyrosequencing. These probes were analysed on a cohort of patients enriched for BRAF mutations taken from the VICTOR and QUASAR2 studies.
  
  
  RESULTS
  In an analysis of 91 tumours (9 BRAF mutant, 82 wild type), the Illumina probe cg11835197 was the probe identified as top differentially methylated (p = 2.56×10-7, Bayes Factor (BF) =6.54). This probe covered a region -413bp from the promoter region of TFAP2E. We found a complex pattern of CpG specific methylation of this region which was associated with both overall (p=0.044) and disease free (p=0.046) survival.
  
  
  CONCLUSIONS
  BRAF mutant tumours may attain part of their chemoresistance from abnormal TFAP2E methylation, which has not previously been described.
authors.affiliation: Translational Surgical Biology Laboratory, School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Beggs
authors.affiliation: Translational Surgical Biology Laboratory, School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Dilworth
authors.affiliation: Molecular & Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Enric
authors.initials: E
authors.lastname: Domingo
authors.affiliation: Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Midgley
authors.affiliation: Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: David
authors.initials: D
authors.lastname: Kerr
authors.affiliation: Molecular & Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Middleton
keywords: BRAF mutation; TFAP2E; Wnt signalling; chemoresistance