Li Lian, Zheng Hong, Huang Yubei, Huang Caiyun, Zhang Shuang, Tian Jing, Li Pei, Sood Anil K, Zhang Wei, Chen Kexin
Department of Epidemiology and Biostatistics, Department of Urology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
Gynecologic Oncology and Reproductive Medicine and Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Carcinogenesis. 2017 Aug 1;38(8):797-805. doi: 10.1093/carcin/bgx057.
Solid tumors are increasingly recognized as a systemic disease that is manifested by changes in DNA, RNA, proteins and metabolites in the blood. Whereas many studies have reported gene mutation events in the circulation, few studies have focused on epigenetic DNA methylation markers. To identify DNA methylation biomarkers in peripheral blood for ovarian cancer, we performed a two-stage epigenome-wide association study. In the discovery stage, we measured genome wide DNA methylation for 485 000 CpG sites in peripheral blood in 24 epithelial ovarian cancer (EOC) cases and 24 age-matched healthy controls. We selected 96 significantly differentially methylated CpG sites for validation using Illumina's Custom VeraCode methylation assay in 206 EOC cases and 205 controls and 46 CpG sites validated in the independent replication samples. A set of 6 of these 46 CpG sites was found by the receiver operating characteristic analysis to have a prediction accuracy of 77.3% for all EOC (95% confidence interval: 72.9-81.8%). Pathway analysis of the genes associated with the 46 CpG sites revealed an enrichment of immune system process genes, including LYST (cg16962115, FDR = 1.24E-04), CADM1 (cg21933078, FDR = 1.22E-02) and NFATC1 (cg06784563, FDR = 1.46E-02). Furthermore, DNA methylation status in peripheral blood was correlated with platelet parameters/coagulation factor levels. This study discovered a panel of epigenetic liquid biopsy markers closely associated with overall immunologic conditions and platelet parameters/coagulation systems of the patients for detection of all stages and subtypes of EOC.
实体瘤越来越被认为是一种全身性疾病，其表现为血液中DNA、RNA、蛋白质和代谢物的变化。尽管许多研究报告了循环中的基因突变事件，但很少有研究关注表观遗传DNA甲基化标记。为了鉴定外周血中卵巢癌的DNA甲基化生物标志物，我们进行了一项两阶段的全表观基因组关联研究。在发现阶段，我们测量了24例上皮性卵巢癌（EOC）患者和24例年龄匹配的健康对照外周血中485000个CpG位点的全基因组DNA甲基化。我们选择了96个差异甲基化显著的CpG位点，使用Illumina的定制VeraCode甲基化检测法在206例EOC患者和205例对照中进行验证，其中46个CpG位点在独立复制样本中得到验证。通过接受者操作特征分析发现，这46个CpG位点中的一组6个位点对所有EOC的预测准确率为77.3%（95%置信区间：72.9 - 81.8%）。对与这46个CpG位点相关的基因进行通路分析，发现免疫系统过程基因富集，包括LYST（cg16962115，FDR = 1.24E - 04）、CADM1（cg21933078，FDR = 1.22E - 02）和NFATC1（cg06784563，FDR = 1.46E - 02）。此外，外周血中的DNA甲基化状态与血小板参数/凝血因子水平相关。本研究发现了一组表观遗传液体活检标志物，与患者的整体免疫状况和血小板参数/凝血系统密切相关，可用于检测EOC的所有阶段和亚型。
