Shridhar Krithiga, Walia Gagandeep Kaur, Aggarwal Aastha, Gulati Smriti, Geetha A V, Prabhakaran Dorairaj, Dhillon Preet K, Rajaraman Preetha
Centre for Chronic Conditions and Injuries, Public Health Foundation of India, Gurgaon, Haryana, India.
Centre for Chronic Conditions and Injuries, Public Health Foundation of India, Gurgaon, Haryana, India.
Oral Oncol. 2016 Feb;53:1-9. doi: 10.1016/j.oraloncology.2015.11.012. Epub 2015 Dec 12.
Although oral cancers are generally preceded by a well-established pre-cancerous stage, there is a lack of well-defined clinical and morphological criteria to detect and signal progression from pre-cancer to malignant tumours. We conducted a critical review to summarize the evidence regarding aberrant DNA methylation patterns as a potential diagnostic biomarker predicting progression. We identified all relevant human studies published in English prior to 30th April 2015 that examined DNA methylation (%) in oral pre-cancer by searching PubMed, Web-of-Science and Embase databases using combined key-searches. Twenty-one studies (18-cross-sectional; 3-longitudinal) were eligible for inclusion in the review, with sample sizes ranging from 4 to 156 affected cases. Eligible studies examined promoter region hyper-methylation of tumour suppressor genes in pathways including cell-cycle-control (n=15), DNA-repair (n=7), cell-cycle-signalling (n=4) and apoptosis (n=3). Hyper-methylated loci reported in three or more studies included p16, p14, MGMT and DAPK. Two longitudinal studies reported greater p16 hyper-methylation in pre-cancerous lesions transformed to malignancy compared to lesions that regressed (57-63.6% versus 8-32.1%; p<0.01). The one study that explored epigenome-wide methylation patterns reported three novel hyper-methylated loci (TRHDE; ZNF454; KCNAB3). The majority of reviewed studies were small, cross-sectional studies with poorly defined control groups and lacking validation. Whilst limitations in sample size and study design preclude definitive conclusions, current evidence suggests a potential utility of DNA methylation patterns as a diagnostic biomarker for oral pre-cancer progression. Robust studies such as large epigenome-wide methylation explorations of oral pre-cancer with longitudinal tracking are needed to validate the currently reported signals and identify new risk-loci and the biological pathways of disease progression.
尽管口腔癌通常有一个已明确的癌前阶段，但缺乏明确的临床和形态学标准来检测并提示从癌前病变进展为恶性肿瘤。我们进行了一项批判性综述，以总结关于异常DNA甲基化模式作为预测进展的潜在诊断生物标志物的证据。我们通过使用组合关键词搜索PubMed、科学网和Embase数据库，确定了2015年4月30日前发表的所有相关英文人类研究，这些研究检测了口腔癌前病变中的DNA甲基化（%）。21项研究（18项横断面研究；3项纵向研究）符合纳入综述的条件，样本量从4例到156例受影响病例不等。符合条件的研究检测了细胞周期控制（n = 15）、DNA修复（n = 7）、细胞周期信号传导（n = 4）和凋亡（n = 3）等途径中肿瘤抑制基因的启动子区域高甲基化。三项或更多研究报道的高甲基化位点包括p16、p14、MGMT和DAPK。两项纵向研究报告，与消退的病变相比，转化为恶性肿瘤的癌前病变中p16高甲基化程度更高（57 - 63.6%对8 - 32.1%；p<0.01）。一项探索全基因组甲基化模式的研究报告了三个新的高甲基化位点（TRHDE；ZNF454；KCNAB3）。大多数综述研究是小型横断面研究，对照组定义不明确且缺乏验证。虽然样本量和研究设计的局限性妨碍得出明确结论，但目前的证据表明DNA甲基化模式作为口腔癌前病变进展的诊断生物标志物具有潜在用途。需要进行如对口腔癌前病变进行大规模全基因组甲基化探索并进行纵向跟踪等有力研究，以验证目前报道的信号，并确定新的风险位点和疾病进展的生物学途径。
