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Background  Oral squamous cell carcinoma (OSCC) is usually diagnosed at an advanced stage and is commonly preceded by oral premalignant lesions. The mortality rates have remained unchanged (50% within 5 years after diagnosis), and it is related to tobacco smoking and alcohol intake. Novel molecular markers for early diagnosis are urgently needed. The purpose of this study was to evaluate the diagnostic value of methylation level in a set of 18 genes by bisulfite next-generation sequencing.    Methods  With minimally invasive oral brushing, 28 consecutive OSCC, one squamous cell carcinoma with sarcomatoid features, six high-grade squamous intraepithelial lesions (HGSIL), 30 normal contralateral mucosa from the same patients, and 65 healthy donors were evaluated for DNA methylation analyzing 18 target genes by quantitative bisulfite next-generation sequencing. We further evaluated an independent cohort (validation dataset) made of 20 normal donors, one oral fibroma, 14 oral lichen planus (OLP), three proliferative verrucous leukoplakia (PVL), and two OSCC.    Results  Comparing OSCC with normal healthy donors and contralateral mucosa in 355 CpGs, we identified the following epigenetically altered genes:  ZAP70 ,  ITGA4 ,  KIF1A ,  PARP15 ,  EPHX3 ,  NTM ,  LRRTM1 ,  FLI1 ,  MIR193 ,  LINC00599 ,  PAX1 , and  MIR137HG  showing hypermethylation and  MIR296 ,  TERT , and  GP1BB  showing hypomethylation .  The behavior of  ZAP70 ,  GP1BB ,  H19 ,  EPHX3 , and  MIR193  fluctuated among different interrogated CpGs. The gap between normal and OSCC samples remained mostly the same (Kruskal-Wallis  P  values < 0.05), but the absolute values changed conspicuously. ROC curve analysis identified the most informative CpGs, and we correctly stratified OSCC and HGSIL from normal donors using a multiclass linear discriminant analysis in a 13-gene panel (AUC 0.981). Only the OSCC with sarcomatoid features was negative. Three contralateral mucosa were positive, a sign of a possible field cancerization. Among imprinted genes, only  MIR296  showed loss of imprinting.  DNMT1 ,  TERC , and  H19  together with the global methylation of  long interspersed element 1  were unchanged. In the validation dataset, values over the threshold were detected in 2/2 OSCC, in 3/3 PVL, and in 2/14 OLP.    Conclusions  Our data highlight the importance of CpG location and correct estimation of DNA methylation level for highly accurate early diagnosis of OSCC.    Electronic supplementary material  The online version of this article (doi:10.1186/s13148-017-0386-7) contains supplementary material, which is available to authorized users.

clinical epigenetics

CpG location and methylation level are crucial factors for the early detection of oral squamous cell carcinoma in brushing samples using bisulfite sequencing of a 13-gene panel