Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada.
Oral Oncol. 2013 Nov;49(11):1033-42. doi: 10.1016/j.oraloncology.2013.08.005. Epub 2013 Sep 13.
Earlier studies involving a priori gene selection have identified promoter regions deregulated by DNA methylation changes in oral squamous cell cancers (OSCCs) and precancers. Interrogation of global DNA methylation patterns for such specimens has not been reported, though such analyses are needed to uncover novel molecular factors driving disease.
We evaluated global DNA methylation patterns for 30 biopsies obtained from 10 patients undergoing surgical removal of an OSCC or carcinoma in situ (CIS). From a disease field in each patient, we collected (i) dysplastic, (ii) CIS or OSCC, and (iii) adjacent normal biopsies. DNA isolated from each biopsy was profiled for methylation status using the Illumina HumanMethylation27K platform.
Our data demonstrate that aberrant methylation of promoter CpG islands exists across oral precancer and OSCC genomes. Non-hierarchical clustering of all methylation data revealed distinct methylation patterns between the normal and the CIS/OSCC tissues (with results for dysplastic biopsies split between groups). Multiple genes exhibiting recurrent aberrant DNA methylation were found for both dysplastic and CIS/OSCC groups, and included enrichment for genes found in the WNT and MAPK signaling pathways.
In identifying aberrant DNA methylation at the earliest stages of oral precancer and finding recurring epigenetic disruption of specific genes/pathways across our analyzed cohort, we see evidence that CpG methylation changes may play a role in oral cancer progression and that global DNA methylation analyses may have significant utility in wider studies that seek to derive biomarkers or potentially druggable targets to improve oral cancer outcomes.
先前涉及先验基因选择的研究已经确定了口腔鳞状细胞癌（OSCC）和癌前病变中 DNA 甲基化变化失调的启动子区域。尽管需要进行此类分析以发现驱动疾病的新分子因素，但尚未报道对这些标本进行全基因组 DNA 甲基化模式的分析。
我们评估了 10 名接受手术切除 OSCC 或原位癌（CIS）的患者中 30 个活检样本的全基因组 DNA 甲基化模式。从每位患者的疾病部位，我们收集了（i）发育不良、（ii）CIS 或 OSCC 以及（iii）相邻正常活检。使用 Illumina HumanMethylation27K 平台对从每个活检分离的 DNA 进行甲基化状态分析。
我们的数据表明，启动子 CpG 岛的异常甲基化存在于口腔癌前病变和 OSCC 基因组中。所有甲基化数据的非层次聚类显示了正常组织和 CIS/OSCC 组织之间存在明显的甲基化模式（发育不良活检的结果在两组之间分裂）。在发育不良和 CIS/OSCC 组中都发现了多个表现出反复异常 DNA 甲基化的基因，包括在 WNT 和 MAPK 信号通路中发现的基因富集。
在识别口腔癌前病变的最早阶段的异常 DNA 甲基化并在我们分析的队列中发现特定基因/通路的反复表观遗传破坏时，我们看到 CpG 甲基化变化可能在口腔癌进展中发挥作用的证据，并且全基因组 DNA 甲基化分析可能在更广泛的研究中具有重要用途，这些研究旨在寻找生物标志物或潜在的可药物靶点，以改善口腔癌的预后。
