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Association of CpG island methylator phenotype and EREG/AREG methylation and expression in colorectal cancer
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Association of CpG island methylator phenotype and EREG/AREG methylation and expression in colorectal cancer
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Association of CpG island methylator phenotype and EREG/AREG methylation and expression in colorectal cancer
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Journal Article
Association of CpG island methylator phenotype and EREG/AREG methylation and expression in colorectal cancer
2016
Overview
Background:
High
EREG
and
AREG
expression, and left-sided primary tumours are associated with superior efficacy of anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (CRC), but a unifying explanation of these findings is lacking.
Methods:
RNA-seq, gene expression arrays, and DNA methylation profiling were completed on 179 CRC tumours. Results were validated using independent The Cancer Genome Atlas data sets. An independent cohort of 198
KRAS
wild-type metastatic CRC tumours was tested for CpG island methylator phenotype (CIMP) status, and progression-free survival (PFS) with the first anti-EGFR regimen was retrospectively determined.
Results:
EREG
and
AREG
expression was highly inversely correlated with methylation and was inversely associated with right-sided primary tumour,
BRAF
mutation, and CIMP-high status. Treatment of CRC cell lines with hypomethylating agents decreased methylation and increased expression of
EREG
. Inferior PFS with anti-EGFR therapy was associated with CIMP-high status,
BRAF
mutation,
NRAS
mutation, and right-sided primary tumour on univariate analysis. Among known
BRAF
/
NRAS
wild-type tumours, inferior PFS remained associated with CIMP-high status (median PFS 5.6
vs
9.0 mo,
P
=0.023).
Conclusions:
EREG
and
AREG
are strongly regulated by methylation, and their expression is associated with CIMP status and primary tumour site, which may explain the association of primary tumour site and
EREG
/
AREG
expression with anti-EGFR therapy efficacy.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Biomedical and Life Sciences
/ Colorectal Neoplasms - drug therapy
/ Colorectal Neoplasms - genetics
/ Colorectal Neoplasms - metabolism
/ Colorectal Neoplasms - pathology
/ Genomes
/ Humans
/ Ligands
/ Male
/ Mutation
/ Oncology
/ Patients
/ Proto-Oncogene Proteins p21(ras) - biosynthesis
/ Proto-Oncogene Proteins p21(ras) - genetics
/ Receptor, Epidermal Growth Factor - antagonists & inhibitors
/ Tumors
