Adenocarcinoma of the stomach and esophagogastric junction with low DNA methylation show poor prognoses
Adenocarcinoma of the stomach and esophagogastric junction with low DNA methylation show poor prognoses
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DOI：
10.1007/s10120-022-01344-3
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发表时间：
2022-10-12
期刊：
影响因子：
7.4
通讯作者：
Kaneda, Atsushi
中科院分区：
文献类型：
--
作者：
Urabe, Masayuki;Matsusaka, Keisuke;Kaneda, Atsushi
背景胃癌（GC）是一种以DNA甲基化表观基因型（MEs）为特征的恶性肿瘤。然而，包括食管胃交界处腺癌（AEG）和背景非肿瘤性柱状粘膜（NM）在内的ME仍有待澄清。方法我们使用Infinium 450 k微珠阵列分析AEG、GC和背景NM的全基因组DNA ME，然后进行定量焦磷酸测序验证。还审查了癌症基因组图谱（TCGA）的大规模数据。结果利用Infinium数据对21个AEG、30个GC和11个NM进行无监督双向层次聚类，得到4种DNA ME：极高ME（E-HME）、高ME（HME）、低ME（LME）和极低ME（E-LME）。在146个样品中通过焦磷酸测序验证启动子甲基化水平。非炎性正常粘膜聚集成E-LME，而胃或食管胃交界处粘膜与幽门螺杆菌感染或反流性食管炎引起的慢性炎症变化聚集在一起，进入LME，表明炎症状态决定DNA ME，无论原因。三例巴雷特相关腺癌病例聚集在HME中。在94例肿瘤可聚类为4个ME之一的患者中，11例E-LME癌患者的总生存期显著短于其他ME，即使采用多变量考克斯回归估计。TCGA数据还显示AEG在HME中富集，而在E-LME中预后较差。结论E-LME是一种独特的亚型，预后不良，与炎症相关的DNA甲基化水平升高无关。LME可以通过慢性炎症获得，无论原因如何，AEG可能优先显示HME。
Background Gastric cancer (GC) is characterized by unique DNA methylation epigenotypes (MEs). However, MEs including adenocarcinomas of the esophagogastric junction (AEG) and background non-neoplastic columnar mucosae (NM) remain to be clarified. Methods We analyzed the genome-wide DNA MEs of AEG, GC, and background NM using the Infinium 450 k beadarray, followed by quantitative pyrosequencing validation. Large-scale data from The Cancer Genome Atlas (TCGA) were also reviewed. Results Unsupervised two-way hierarchical clustering using Infinium data of 21 AEG, 30 GC, and 11 NM revealed four DNA MEs: extremely high-ME (E-HME), high-ME (HME), low-ME (LME), and extremely low-ME (E-LME). Promoter methylation levels were validated by pyrosequencing in 146 samples. Non-inflammatory normal mucosae were clustered into E-LME, whereas gastric or esophagogastric junction mucosae with chronic inflammatory changes caused by either Helicobacter pylori infection or reflux esophagitis were clustered together into LME, suggesting that inflammation status determined DNA MEs regardless of the cause. Three cases of Barrett's-related adenocarcinoma were clustered into HME. Among 94 patients whose tumors could be clustered into one of four MEs, 11 patients with E-LME cancers showed significantly shorter overall survival than that in the other MEs, even with the multivariate Cox regression estimate. TCGA data also showed enrichment of AEG in HME and a poorer prognosis in E-LME. Conclusions E-LME cases, newly confirmed in this study, form a unique subtype with poor prognosis that is not associated with inflammation-associated elevation of DNA methylation levels. LME could be acquired via chronic inflammation, regardless of the cause, and AEG might preferentially show HME.