Hypermethylation of the nel-like 1 gene is a common and early event and is associated with poor prognosis in early-stage esophageal adenocarcinoma
Hypermethylation of the nel-like 1 gene is a common and early event and is associated with poor prognosis in early-stage esophageal adenocarcinoma
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DOI：
10.1038/sj.onc.1210461
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发表时间：
2007-09-20
期刊：
影响因子：
8
通讯作者：
Meltzer, S. J.
中科院分区：
文献类型：
--
作者：
Jin, Z.;Mori, Y.;Meltzer, S. J.
nel-like1 （NELL1）基因定位于11p15染色体，该染色体在食管癌（EAC）中经常发生杂合性缺失。采用实时甲基化特异性聚合酶链反应检测259例人食管组织NELL1启动子超甲基化。该启动子的高甲基化表现出高度判别性的受体-操作者特征曲线pro。食管鳞状细胞癌（ESCC）和食管鳞状细胞癌（EAC）与正常食管（NE）的差异有统计学意义（P < 0.001）。NELL1标准化甲基化值在Barrett’s化生（BE）、发育不良Barrett’s (D)和EAC中显著高于NE （P < 0.0000001）。NE患者的NELL1超甲基化频率为零，但在肿瘤进展早期增加，仅Barrett患者的BE为41.7%，D为52.5%，EAC为47.8%。NELL1高甲基化与BE片段长度有显著相关。26例escc中有3例（11.5%）表现出NELL1高甲基化。I-II期EAC患者的生存与NELL1高甲基化呈负相关（P = 0.0264），而III-IV期EAC患者的生存与NELL1高甲基化呈负相关（P = 0.68）。5-aza-2'-脱氧胞苷处理KYSE220 ESCC和BIC EAC细胞可降低NELL1甲基化，增加NELL1 mRNA表达。NELL1启动子未甲基化的EACs中NELL1 mRNA水平显著高于启动子甲基化的EACs （P < 0.02）。NELL1启动子高甲基化是人类EAC中常见的组织特异性事件，发生在Barrett相关食管肿瘤进展的早期，是早期EAC预后不良的潜在生物标志物。
The nel-like1 ( NELL1) gene maps to chromosome 11p15, which frequently undergoes loss of heterozygosity in esophageal adenocarcinoma ( EAC). NELL1 promoter hypermethylation was examined by real-time methylation-specific polymerase chain reaction in 259 human esophageal tissues. Hypermethylation of this promoter showed highly discriminative receiver-operator characteristic curve pro. les, clearly distinguishing esophageal squamous cell carcinoma ( ESCC) and EAC from normal esophagus ( NE) ( P < 0.001). NELL1 normalized methylation values were significantly higher in Barrett's metaplasia ( BE), dysplastic Barrett's ( D) and EAC than in NE ( P < 0.0000001). NELL1 hypermethylation frequency was zero in NE but increased early during neoplastic progression, to 41.7% in BE from patients with Barrett's alone, 52.5% in D and 47.8% in EAC. There was a significantly correlation between NELL1 hypermethylation and BE segment length. Three ( 11.5%) of 26 ESCCs exhibited NELL1 hypermethylation. Survival correlated inversely with NELL1 hypermethylation in patients with stages I-II (P = 0.0264) but not in stages III-IV ( P = 0.68) EAC. Treatment of KYSE220 ESCC and BIC EAC cells with 5-aza-2'-deoxycytidine reduced NELL1 methylation and increased NELL1 mRNA expression. NELL1 mRNA levels in EACs with an unmethylated NELL1 promoter were significantly higher than those in EACs with a methylated promoter ( P 0.02). Promoter hypermethylation of NELL1 is a common, tissue-specific event in human EAC, occurs early during Barrett's-associated esophageal neoplastic progression, and is a potential biomarker of poor prognosis in early-stage EAC.