参与三项独立、随机、开放标签临床试验的转移性结直肠癌患者中参与调节 DNA 甲基化的基因多态性的影响：TRIBE、MAVERICC 和 FIRE-3 的荟萃分析。
Impact of polymorphisms within genes involved in regulating DNA methylation in patients with metastatic colorectal cancer enrolled in three independent, randomised, open-label clinical trials: a meta-analysis from TRIBE, MAVERICC and FIRE-3.
机构信息
Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Clinical and Experimental Oncology Department, Medical Oncology Unit 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
出版信息
Eur J Cancer. 2019 Apr;111:138-147. doi: 10.1016/j.ejca.2019.01.105. Epub 2019 Mar 7.
BACKGROUND
CpG island DNA hypermethylation and global DNA hypomethylation are hallmark characteristics of colorectal cancer (CRC). Therefore, we aim to explore the effect of genetic variations within the genes that regulate the DNA methylation and demethylation pathways on outcomes in patients with metastatic CRC (mCRC) treated with first-line therapy and enrolled in three independent, randomised, open-label clinical trials.
METHODS
A total of 884 patients with mCRC enrolled in TRIBE, MAVERICC and FIRE-3 trials were included. Single-nucleotide polymorphisms (SNPs) within genes involved in DNA methylation and demethylation pathways were analysed. The prognostic value of each SNP across all treatment arms was quantified using the inverse-variance-weighted effect size, a meta-analysis approach implemented in the METASOFT software.
RESULTS
In the meta-analysis, DNMT3A rs11681717 was significantly associated with overall survival (hazard ratio = 1.26; 95% confidence interval [CI] 1.08-1.46; P = 0.002; false discovery rate [FDR] = 0.016), accounting for seven tests in the DNA methylation pathway. In addition, there was suggestive evidence of association for ten-eleven translocation (TET) genes variance with tumour response (TET1 rs3814177, odds ratio [OR] = 0.76, 95% CI 0.59-0.97, P = 0.025, FDR = 0.087; TET3 rs7560668, OR = 1.44; 95% CI 1.10-1.89; P = 0.009; FDR = 0.062).
CONCLUSIONS
We showed that polymorphisms within the genes responsible for the DNA methylation and demethylation machineries are correlated with outcomes in patients with mCRC who were enrolled in three independent, randomised, open-label, phase II/III clinical trials. In addition, we demonstrated the feasibility of a meta-analysis approach to identify stronger and more convincing association between gene polymorphisms and outcome, potentially leading the way to a new method of analysis for similar data set.
背景
CpG 岛 DNA 超甲基化和全基因组 DNA 低甲基化是结直肠癌（CRC）的标志性特征。因此，我们旨在探索调节 DNA 甲基化和去甲基化途径的基因内遗传变异对接受一线治疗并纳入三项独立、随机、开放标签临床试验的转移性结直肠癌（mCRC）患者结局的影响。
方法
共纳入 TRIBE、MAVERICC 和 FIRE-3 试验中 884 例 mCRC 患者。分析 DNA 甲基化和去甲基化途径相关基因中的单核苷酸多态性（SNP）。使用逆方差加权效应大小（在 METASOFT 软件中实现的荟萃分析方法）量化每个 SNP 在所有治疗组中的预后价值。
结果
荟萃分析中，DNMT3A rs11681717 与总生存期显著相关（风险比=1.26；95%置信区间[CI] 1.08-1.46；P=0.002；假发现率[FDR] = 0.016），该 SNP 代表 DNA 甲基化途径中的 7 项检测。此外，十号染色体缺失易位基因（TET）变异与肿瘤反应之间存在提示性关联的证据（TET1 rs3814177，比值比[OR] = 0.76，95%CI 0.59-0.97，P=0.025，FDR = 0.087；TET3 rs7560668，OR = 1.44；95%CI 1.10-1.89；P=0.009；FDR = 0.062）。
结论
我们表明，负责 DNA 甲基化和去甲基化机制的基因内的多态性与纳入三项独立、随机、开放标签、Ⅱ/Ⅲ期临床试验的 mCRC 患者的结局相关。此外，我们证明了荟萃分析方法识别基因多态性与结局之间更强、更有说服力的关联的可行性，这可能为类似数据集的新分析方法铺平了道路。
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