Methylation changes in the TFAP2E promoter region are associated with BRAF mutation and poorer overall & disease free survival in colorectal cancer
Andrew D. Beggs1, Mark P. Dilworth1, Enric Domingo2, Rachel Midgley3, David Kerr3, Ian P.M. Tomlinson2, Gary W. Middleton4
1 Translational Surgical Biology Laboratory, School of Cancer Sciences, University of Birmingham
2 Molecular & Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford
3 Department of Oncology, University of Oxford
4 School of Cancer Sciences, University of Birmingham
Andrew Beggs, email:
Keywords: BRAF mutation, chemoresistance, TFAP2E, Wnt signalling
Received: January 20, 2015 Accepted: March 16, 2015 Published: March 23, 2015
Introduction: 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 = 2.56x10-7, 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.
Discussion: BRAF mutant tumours may attain part of their chemoresistance from abnormal TFAP2E methylation, which has not previously been described.