Worsham Maria J, Chen Kang Mei, Datta Indrani, Stephen Josena K, Chitale Dhananjay, Gothard Alexandra, Divine George
Department of Otolaryngology/Head and Neck Research, Henry Ford Hospital, Detroit, MI 48202, USA.
Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI 48202, USA.
Oncol Lett. 2016 Dec;12(6):4949-4956. doi: 10.3892/ol.2016.5303. Epub 2016 Oct 21.
In recent years, studies have suggested that promoter methylation in human papilloma virus (HPV) positive head and neck squamous cell carcinoma (HNSCC) has a mechanistic role and has the potential to improve patient survival. The present study aimed to replicate key molecular findings from previous analyses of the methylomes of HPV positive and HPV negative HNSCC in an independent cohort, to assess the reliability of differentially methylated markers in HPV-associated tumors. HPV was measured using real-time quantitative PCR and the biological significance of methylation differences was assessed by Ingenuity Pathway Analysis (IPA). Using an identical experimental design of a 450K methylation platform, 7 of the 11 genes were detected to be significantly differentially methylated and all 11 genes were either hypo- or hypermethylated, which was in agreement with the results of a previous study. IPA's enriched networks analysis identified one network with msh homeobox 2 (MSX2) as a central node. Locally dense interactions between genes in networks tend to reflect significant biology; therefore MSX2 was selected as an important gene. Sequestration in the top four canonical pathways was noted for 5-hydroxytryptamine receptor 1E (serotonin signaling), collapsin response mediator protein 1 (semaphorin signaling) and paired like homeodomain 2 (bone morphogenic protein and transforming growth factor-β signaling). Placement of 9 of the 11 genes in highly ranked pathways and bionetworks identified key biological processes to further emphasize differences between HNSCC HPV positive and negative pathogenesis.
近年来，研究表明人乳头瘤病毒（HPV）阳性的头颈部鳞状细胞癌（HNSCC）中的启动子甲基化具有机制性作用，并且有可能改善患者生存率。本研究旨在独立队列中重复先前对HPV阳性和HPV阴性HNSCC甲基化组分析的关键分子发现，以评估HPV相关肿瘤中差异甲基化标志物的可靠性。使用实时定量PCR检测HPV，并通过 Ingenuity 通路分析（IPA）评估甲基化差异的生物学意义。采用相同的450K甲基化平台实验设计，检测到11个基因中的7个存在显著差异甲基化，并且所有11个基因均为低甲基化或高甲基化，这与先前的研究结果一致。IPA的富集网络分析确定了一个以MSX2（msh同源盒2）为中心节点的网络。网络中基因之间的局部密集相互作用往往反映了重要的生物学特性；因此，MSX2被选为重要基因。在5-羟色胺受体1E（血清素信号传导）、塌陷反应介导蛋白1（信号素信号传导）和配对样同源结构域2（骨形态发生蛋白和转化生长因子-β信号传导）的前四个经典通路中发现了隔离现象。11个基因中的9个在高度排名的通路和生物网络中的定位确定了关键生物学过程，进一步强调了HPV阳性和阴性HNSCC发病机制之间的差异。
