New DNA methylation markers and global DNA hypomethylation are associated with oral cancer development.
New DNA methylation markers and global DNA hypomethylation are associated with oral cancer development.
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DOI：
10.1158/1940-6207.capr-14-0179
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发表时间：
2015-11
期刊：
影响因子：
--
通讯作者：
Saintigny P
中科院分区：
文献类型：
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作者：
Foy JP;Pickering CR;Papadimitrakopoulou VA;Jelinek J;Lin SH;William WN Jr;Frederick MJ;Wang J;Lang W;Feng L;Zhang L;Kim ES;Fan YH;Hong WK;El-Naggar AK;Lee JJ;Myers JN;Issa JP;Lippman SM;Mao L;Saintigny P
肿瘤抑制基因的DNA启动子甲基化和整体DNA低甲基化是头颈癌的共同特征。我们的目标是确定口腔癌前病变（opl）的早期DNA甲基化变化，这可能作为发展为口腔鳞状细胞癌（OSCC）的预测标志物。利用24个opl的高通量DNA甲基化谱，我们发现发生或未发生OSCC的患者之间甲基化差异最大的86个基因同时发生高甲基化，这表明CpG岛甲基化表型可能发生在OSCC发展的早期。86个基因中的绝大多数在正常组织中未甲基化，而在OSCC中与正常粘膜相比呈高甲基化。我们在44名患者的验证队列中使用磷酸氢测序来评估前86个基因中AGTR1、FOXI2和PENK启动子CpG位点的甲基化程度，以及LINE1重复元件甲基化的程度，LINE1重复元件甲基化是全球DNA甲基化的替代。通过平均AGTR1、FOXI2和PENK启动子的甲基化百分比，建立了甲基化指数（MI）；心肌梗死高的患者OCFS较差（P=0.0030）。另一方面，LINE1甲基化水平低的患者OCFS明显较差（P=0.0153）。总之，AGTR1、FOXI2和PENK启动子甲基化和LINE1低甲基化可能与opl患者发生OSCC的风险增加有关。
DNA promoter methylation of tumor suppressor genes and global DNA hypomethylation are common features of head and neck cancers. Our goal was to identify early DNA methylation changes in oral premalignant lesions (OPLs) that may serve as predictive markers of developing oral squamous cell carcinoma (OSCC). Using high-throughput DNA methylation profiles of 24 OPLs, we found that the top 86 genes differentially methylated between patients who did or did not develop OSCC were simultaneously hypermethylated, suggesting that a CpG island methylation phenotype may occur early during OSCC development. The vast majority of the 86 genes were non-methylated in normal tissues and hypermethylated in OSCC versus normal mucosa. We used pyrosequencing in a validation cohort of 44 patients to evaluate the degree of methylation of AGTR1, FOXI2, and PENK promoters CpG sites that were included in the top 86 genes, and of LINE1 repetitive element methylation, a surrogate of global DNA methylation. A Methylation Index (MI) was developed by averaging the percent methylation of AGTR1, FOXI2, and PENK promoters; patients with a high MI had a worse OCFS (P=0.0030). On the other hand, patients with low levels of LINE1 methylation had a significantly worse OCFS (P=0.0153). In conclusion, AGTR1, FOXI2 and PENK promoter methylation and LINE1 hypomethylation may be associated with an increased risk of OSCC development in patients with OPLs.