TY - JOUR
T1 - Association of CpG island methylator phenotype and EREG/AREG methylation and expression in colorectal cancer
AU - Lee, Michael S.
AU - McGuffey, Elizabeth J.
AU - Morris, Jeffrey S.
AU - Manyam, Ganiraju
AU - Baladandayuthapani, Veerabahdran
AU - Wei, Wei
AU - Morris, Van K.
AU - Overman, Michael J.
AU - Maru, Dipen M.
AU - Jiang, Zhi Qin
AU - Hamilton, Stanley R.
AU - Kopetz, Scott
N1 - Funding Information:
ACKNOWLEDGEMENTS: This research was supported by American Society of Clinical Oncology Conquer Cancer Foundation Young Investigator Awards individually granted to MSL and VKM; NIH R01 CA160736 (to VB); NCI Cancer Center Support Grant (CCSG) P30 CA016672 (to VB, WW, and SK); NIH R01 CA172670 (to SK), and NIH R01 CA184843 (to SK).
PY - 2016/6/14
Y1 - 2016/6/14
N2 - 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.
AB - 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.
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U2 - 10.1038/bjc.2016.87
DO - 10.1038/bjc.2016.87
M3 - Article
C2 - 27272216
AN - SCOPUS:84973402587
SN - 0007-0920
VL - 114
SP - 1352
EP - 1361
JO - British journal of cancer
JF - British journal of cancer
IS - 12
ER -