Association of CpG island methylator phenotype and EREG/AREG methylation and expression in colorectal cancer

被引:80
作者
Lee, Michael S. [1 ,2 ]
McGuffey, Elizabeth J. [3 ]
Morris, Jeffrey S. [4 ]
Manyam, Ganiraju [4 ]
Baladandayuthapani, Veerabahdran [4 ]
Wei, Wei [4 ]
Morris, Van K. [5 ]
Overman, Michael J. [5 ]
Maru, Dipen M. [6 ]
Jiang, Zhi-Qin [5 ]
Hamilton, Stanley R. [6 ]
Kopetz, Scott [5 ]
机构
[1] Univ N Carolina, Dept Med, Div Hematol Oncol, 170 Manning Dr,CB 7305, Chapel Hill, NC 27599 USA
[2] Lineberger Comprehens Canc Ctr, 170 Manning Dr,CB 7295, Chapel Hill, NC 27599 USA
[3] US Naval Acad, Dept Math, 572C Holloway Rd, Annapolis, MD 21402 USA
[4] Univ Texas MD Anderson Canc Ctr, Dept Biostat, 1515 Holcombe Blvd, Houston, TX 77030 USA
[5] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA
[6] Univ Texas MD Anderson Canc Ctr, Dept Pathol, 1515 Holcombe Blvd, Houston, TX 77030 USA
关键词
EREG; AREG; CIMP; cetuximab; methylation; GENE-EXPRESSION; 1ST-LINE TREATMENT; DNA METHYLATION; PLUS IRINOTECAN; PRIMARY TUMORS; RAS MUTATIONS; CETUXIMAB; BENEFIT; KRAS; CHEMOTHERAPY;
D O I
10.1038/bjc.2016.87
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:1352 / 1361
页数:10
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