DNA hypomethylation-related overexpression of SFN, GORASP2 and ZYG11A is a novel prognostic biomarker for early stage lung adenocarcinoma.
DNA hypomethylation-related overexpression of SFN, GORASP2 and ZYG11A is a novel prognostic biomarker for early stage lung adenocarcinoma.
复制标题
DOI：
10.18632/oncotarget.26676
复制
发表时间：
2019-02-26
期刊：
影响因子：
--
通讯作者：
Noguchi, Masayuki
中科院分区：
文献类型：
--
作者：
Husni, Ryan Edbert;Shiba-Ishii, Aya;Noguchi, Masayuki
虽然晚期癌症中DNA甲基化的改变已被广泛研究，但早期肺腺癌的数据很少。在这里，我们使用Infinium甲基化阵列比较原位腺癌（AIS）和早期浸润性腺癌之间的DNA甲基化谱，以研究导致腺癌早期进展的甲基化异常。我们重点研究了位于启动子CpG岛或海岸区域的差异甲基化位点，并在早期浸润性腺癌中鉴定了579个高甲基化位点和23个低甲基化位点。这些高甲基化基因与神经元通路如GABA受体和5-羟色胺信号通路显著相关。在低甲基化基因中，我们发现GORASP 2、ZYG 11 A和SFN在海岸区域具有显著较低的甲基化率，而在浸润性腺癌中具有显著较高的蛋白表达。此外，这些蛋白质的过度表达与患者的不良结局密切相关。尽管相对于DNA高甲基化，启动子区域的DNA去甲基化可能是罕见的，但我们发现了2个新基因GORASP 2和ZYG 11 A，它们在浸润性腺癌中表现出低甲基化和过表达，这表明它们在肿瘤细胞中具有重要功能。这些基因可作为临床预后指标，并可能成为药物开发的潜在新靶分子。
Although alteration of DNA methylation in advanced cancer has been extensively investigated, few data for early-stage lung adenocarcinoma are available. Here, we compared DNA methylation profiles between adenocarcinoma in situ (AIS) and early invasive adenocarcinoma using the Infinium methylation array to investigate methylation abnormalities causing early progression of adenocarcinomas. We focused on differentially methylated sites which were located in promoter CpG islands or shore regions, and identified 579 hypermethylated sites and 23 hypomethylated sites in early invasive adenocarcinoma relative to AIS and normal lung. These hypermethylated genes were significantly associated with neuronal pathways such as the GABA receptor and serotonin signaling pathways. Among the hypomethylated genes, we found that GORASP2, ZYG11A, and SFN had significantly lower methylation rates at the shore regions and significantly higher protein expression in invasive adenocarcinoma. Moreover, overexpression of those proteins was strongly associated with patient's poor outcome. Despite DNA demethylation at the promoter region might be rare relative to DNA hypermethylation, we identified 2 new genes, GORASP2 and ZYG11A, which show hypomethylation and overexpression in invasive adenocarcinoma, suggesting that they have important functions in tumor cells. These genes may be clinically applicable as prognostic indicators and could be potential novel target molecules for drug development.