title: DNA methylation markers for oral pre-cancer progression: A critical review.
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.
authors.affiliation: Centre for Chronic Conditions and Injuries, Public Health Foundation of India, Gurgaon, Haryana, India. Electronic address: g.krithiga@phfi.org.
authors.forename: Krithiga
authors.initials: K
authors.lastname: Shridhar
authors.affiliation: Centre for Chronic Conditions and Injuries, Public Health Foundation of India, Gurgaon, Haryana, India.
authors.forename: Gagandeep Kaur
authors.initials: GK
authors.lastname: Walia
authors.affiliation: Centre for Chronic Conditions and Injuries, Public Health Foundation of India, Gurgaon, Haryana, India.
authors.forename: Aastha
authors.initials: A
authors.lastname: Aggarwal
authors.affiliation: Centre for Chronic Conditions and Injuries, Public Health Foundation of India, Gurgaon, Haryana, India.
authors.forename: Smriti
authors.initials: S
authors.lastname: Gulati
authors.affiliation: Centre for Chronic Conditions and Injuries, Public Health Foundation of India, Gurgaon, Haryana, India.
authors.forename: A V
authors.initials: AV
authors.lastname: Geetha
authors.affiliation: 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.
authors.forename: Dorairaj
authors.initials: D
authors.lastname: Prabhakaran
authors.affiliation: Centre for Chronic Conditions and Injuries, Public Health Foundation of India, Gurgaon, Haryana, India.
authors.forename: Preet K
authors.initials: PK
authors.lastname: Dhillon
authors.affiliation: Center for Global Health, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA.
authors.forename: Preetha
authors.initials: P
authors.lastname: Rajaraman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology; D014408:Biomarkers, Tumor / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology; D002648:Child; D003430:Cross-Sectional Studies; D019175:DNA Methylation / Q000502:physiology*; D004260:DNA Repair; D018450:Disease Progression; D055088:Early Detection of Cancer / Q000379:methods; D019317:Evidence-Based Medicine; D005260:Female; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000473:pathology*; D011230:Precancerous Conditions / Q000175:diagnosis / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor
keywords: Bio-marker; CpG sites; DNA methylation; Diagnostic marker; Epigenetics; Leukoplakia; Oral pre-cancer; Oral sub-mucous fibrosis; Promoter regions; Tumour suppressor genes