Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
Gastric Cancer. 2022 Mar;25(2):336-345. doi: 10.1007/s10120-021-01252-y. Epub 2021 Sep 23.
Prediction of tissue origin of esophagogastric junction (EGJ) adenocarcinomas can be important for therapeutic decision, but no molecular marker is available. Here, we aimed to develop such a marker taking advantage of tissue-specific profiles of DNA methylation.
DNA methylation profiles of gastric adenocarcinomas (GACs) were obtained by an Infinium HumanMethylation450 BeadChip array, and those of esophageal adenocarcinoma (EACs) were obtained from the TCGA database. DNA from formalin-fixed paraffin-embedded (FFPE) samples was analyzed by bisulfite pyrosequencing.
In the screening set, 51 of 145,841 CpG sites in CpG islands were methylated at significantly higher levels in 30 GACs compared to those in 30 EACs. Among them, SLC46A3 and cg09177106 were unmethylated in all the 30 EACs. Predictive powers of these two markers were successfully confirmed in an independent validation set (18 GACs and 18 EACs) (SLC46A3, sensitivity = 77.8%, specificity = 100%; cg09177106, sensitivity = 83.3%, specificity = 94.4%), and could be applied to FFPE samples (37 GACs and 18 EACs) (SLC46A3, P = 0.0001; cg09177106, P = 0.0028). On the other hand, EAC-specific markers informative in the FFPE samples could not be isolated. Using these GAC-specific markers, nine of 46 (19.6%) TCGA EGJ adenocarcinomas were predicted to be GACs.
Two GAC-specific markers, SLC46A3 and cg09177106, had a high specificity for identifying the tissue origin of EGJ adenocarcinoma.
预测食管胃结合部（EGJ）腺癌的组织来源对于治疗决策很重要，但目前尚无分子标志物可用。在这里，我们旨在利用组织特异性的 DNA 甲基化谱来开发这样的标志物。
通过 Infinium HumanMethylation450 BeadChip 芯片获得胃腺癌（GAC）的 DNA 甲基化谱，从 TCGA 数据库获得食管腺癌（EAC）的 DNA 甲基化谱。对福尔马林固定石蜡包埋（FFPE）样本的 DNA 进行亚硫酸氢盐焦磷酸测序分析。
在筛选集中，与 30 例 EAC 相比，在 30 例 GAC 中，145841 个 CpG 岛中的 51 个 CpG 位点的甲基化水平显著升高。其中，SLC46A3 和 cg09177106 在所有 30 例 EAC 中均未甲基化。这两个标志物的预测能力在独立验证集中（18 例 GAC 和 18 例 EAC）得到了成功验证（SLC46A3，灵敏度=77.8%，特异性=100%；cg09177106，灵敏度=83.3%，特异性=94.4%），并且可应用于 FFPE 样本（37 例 GAC 和 18 例 EAC）（SLC46A3，P=0.0001；cg09177106，P=0.0028）。另一方面，在 FFPE 样本中无法分离出对 EAC 有信息的 EAC 特异性标记物。使用这些 GAC 特异性标记物，在 46 例 TCGA EGJ 腺癌中，有 9 例（19.6%）被预测为 GAC。
两个 GAC 特异性标记物 SLC46A3 和 cg09177106 对于确定 EGJ 腺癌的组织来源具有很高的特异性。
