Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan.
Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan.
Cancer Sci. 2022 Sep;113(9):3221-3233. doi: 10.1111/cas.15367. Epub 2022 Jul 15.
The cetuximab gene expression signature and DNA methylation status of colorectal cancer (CRC) are predictive of the therapeutic effects of anti-epidermal growth factor receptor (EGFR) antibody therapy. As DNA methylation is a means of regulating gene expression, it may play an important role in the expression of cetuximab signature genes. This study aims to determine the effects of aberrant DNA methylation on the regulation of cetuximab signature gene expression. Comprehensive DNA methylation and gene expression data were retrieved from CRC patients in three tumor tissue (TT) cohorts and three normal colorectal mucosa/tumor tissue paired (NCM-TT) cohorts. Of the 231 cetuximab signature genes, 57 exhibited an inverse correlation between the methylation of promoter CpG sites and gene expression level in multiple cohorts. About two-thirds of the promoter CpG sites associated with the 57 genes exhibited this correlation. In all 57 gene promoter regions, the methylation levels in NCMs did not differ according to comparisons based on cetuximab signature or DNA methylation status classification of matched TTs. Thus, the altered expression of 57 genes was caused by aberrant DNA methylation during carcinogenesis. Analysis of the association between cetuximab signature or DNA methylation status and progression-free survival (PFS) of anti-EGFR antibody agents in the same cohort showed that DNA methylation status was most associated with PFS. In conclusion, we found that aberrant DNA methylation regulates specific gene expression in cetuximab signature during carcinogenesis, suggesting that it is one of the important determinants of sensitivity to anti-EGFR antibody agents.
结直肠癌（CRC）的西妥昔单抗基因表达特征和 DNA 甲基化状态可预测抗表皮生长因子受体（EGFR）抗体治疗的疗效。由于 DNA 甲基化是调节基因表达的一种方式，它可能在西妥昔单抗特征基因的表达中发挥重要作用。本研究旨在确定异常 DNA 甲基化对西妥昔单抗特征基因表达调控的影响。从三个肿瘤组织（TT）队列和三个正常结直肠黏膜/肿瘤组织配对（NCM-TT）队列的 CRC 患者中检索了综合 DNA 甲基化和基因表达数据。在 231 个西妥昔单抗特征基因中，有 57 个基因的启动子 CpG 位点的甲基化与多个队列中的基因表达水平呈负相关。与这 57 个基因相关的启动子 CpG 位点中，约有三分之二表现出这种相关性。在所有 57 个基因启动子区域中，NCM 中的甲基化水平在基于西妥昔单抗特征或匹配 TT 的 DNA 甲基化状态分类的比较中没有差异。因此，57 个基因的表达改变是由于致癌过程中异常的 DNA 甲基化所致。对同一队列中西妥昔单抗特征或 DNA 甲基化状态与抗 EGFR 抗体药物无进展生存期（PFS）的相关性分析表明，DNA 甲基化状态与 PFS 最相关。总之，我们发现异常的 DNA 甲基化在致癌过程中调节西妥昔单抗特征中的特定基因表达，表明它是对抗 EGFR 抗体药物敏感性的重要决定因素之一。
