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Oral Oncol. 2016 Feb;53:1-9. doi: 10.1016/j.oraloncology.2015.11.012. Epub 2015 Dec 12.

DNA methylation markers for oral pre-cancer progression: A critical review.

Author information

1
Centre for Chronic Conditions and Injuries, Public Health Foundation of India, Gurgaon, Haryana, India. Electronic address: g.krithiga@phfi.org.
2
Centre for Chronic Conditions and Injuries, Public Health Foundation of India, Gurgaon, Haryana, India.
3
Centre for Chronic Conditions and Injuries, Public Health Foundation of India, Gurgaon, Haryana, India; Centre for Chronic Disease Control, Gurgaon, Haryana, India; London School of Hygiene and Tropical Medicine, London, United Kingdom.
4
Center for Global Health, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA.

Abstract

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.

KEYWORDS:

Bio-marker; CpG sites; DNA methylation; Diagnostic marker; Epigenetics; Leukoplakia; Oral pre-cancer; Oral sub-mucous fibrosis; Promoter regions; Tumour suppressor genes

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