Association of CpG island methylator phenotype and EREG/AREG methylation and expression in colorectal cancer.
Association of CpG island methylator phenotype and EREG/AREG methylation and expression in colorectal cancer.
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DOI：
10.1038/bjc.2016.87
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发表时间：
2016-06-14
影响因子：
8.8
通讯作者：
Kopetz S
中科院分区：
文献类型：
--
作者：
Lee MS;McGuffey EJ;Morris JS;Manyam G;Baladandayuthapani V;Wei W;Morris VK;Overman MJ;Maru DM;Jiang ZQ;Hamilton SR;Kopetz S
EREG和AREG高表达以及左侧原发性肿瘤与抗表皮生长因子受体（EGFR）治疗转移性结直肠癌（CRC）的上级疗效相关，但缺乏对这些结果的统一解释。在179个CRC肿瘤中完成了RNA-seq、基因表达阵列和DNA甲基化分析。使用独立的癌症基因组图谱数据集验证结果。对198例KRAS野生型转移性CRC肿瘤的独立队列进行了CpG岛甲基化表型（CIMP）状态检测，并回顾性确定了首次抗EGFR方案的无进展生存期（PFS）。EREG和AREG表达与甲基化高度负相关，与右侧原发性肿瘤、BRAF突变和CIMP高水平状态呈负相关。用低甲基化剂处理CRC细胞系降低了甲基化并增加了EREG的表达。单变量分析显示，抗EGFR治疗的PFS较差与CIMP高水平状态、BRAF突变、NRAS突变和右侧原发性肿瘤相关。在已知的BRAF/NRAS野生型肿瘤中，较低的PFS仍然与CIMP高状态相关（中位PFS 5.6 vs 9.0个月，P=0.023）。EREG和AREG受甲基化强烈调控，其表达与CIMP状态和原发肿瘤部位相关，这可能解释原发肿瘤部位和EREG/AREG表达与抗EGFR治疗疗效的相关性。
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. 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. 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). 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.