The epigenetic landscape of oral squamous cell carcinoma

Abstract

Background:There is relatively little methylation array data available specifically for oral squamous cell carcinoma (OSCC). This study aims to compare the DNA methylome across a large cohort of tumour/normal pairs.Methods:DNA was extracted from 44 OSCCs and paired normal mucosa. DNA methylation analysis employed the Illumina GoldenGate high-throughput array comprising 1505 CpG loci selected from 807 epigenetically regulated genes. This data was correlated with extracapsular spread (ECS), human papilloma virus (HPV) status, recurrence and 5-year survival.Results:Differential methylation levels of a number of genes distinguished the tumour tissue sample from the matched normal. Putative methylation signatures for ECS and recurrence were identified. The concept of concordant methylation or CpG island methylator phenotype (CIMP) in OSCC is supported by our data, with an association between ‘CIMP-high' and worse prognosis. Epigenetic deregulation of NOTCH4 signalling in OSCC was also observed, as part of a possible methylation signature for recurrence, with parallels to recently discovered NOTCH mutations in HNSCC. Differences in methylation in HPV-driven cases were seen, but are less significant than that has been recently proposed in other series.Conclusion:Although OSCC seems as much an ‘epigenetic' as a genetic disease, the translational potential of cancer epigenetics has yet to be fully exploited. This data points to the application of epigenetic biomarkers and targets available to further the development of therapy in OSCC.

DNA methylation profiles and biomarkers of oral squamous cell carcinoma

“…About one half of the identified genes (e.g., ADCYAP1, FGF3, GAS7, and KDR) also exhibited potential in our tissue samples as biomarkers of oral cancer. In a recent study, Jithesh et al 39 also employed the same array and suggested that EPHA5, GSTM2, HS3ST2, MME, MT1A, MYOD1, NPY, and PENK are potential biomarkers for detecting oral cancer, as in the present study. The only triple-hit gene among the studies of Viet et al, 10 Jithesh et al, 39 and ourselves was EPHA5.…”

“…In a recent study, Jithesh et al 39 also employed the same array and suggested that EPHA5, GSTM2, HS3ST2, MME, MT1A, MYOD1, NPY, and PENK are potential biomarkers for detecting oral cancer, as in the present study. The only triple-hit gene among the studies of Viet et al, 10 Jithesh et al, 39 and ourselves was EPHA5. In addition, Nagata et al 40 reported that the aberrant methylation of a combination of ECAD, TMEFF2, RARb, and MGMT from rinse samples can detect OSCC with a sensitivity and specificity of >90% by using noninvasive methods to retrieve samples and a different methylation platform.…”

Molecular mechanisms of ethanol-associated oro-esophageal squamous cell carcinoma

“…These data suggest that ethanol may contribute to OESCC through aberrant gene methylation [61,62]. In addition, aberrant gene methylation may impact signaling pathways through critical pathway genes, such as Notch4 of the Notch signaling pathway [63], PTEN of the phospoinositide 3-kinase (PI3K)/Akt pathway [64], and Wnt inhibitory factor 1 (WIF1) of the Wnt signaling pathway [65]. Recent studies have also showed that aberrant methylation of histones and non-histone proteins also modulates multiple signaling pathways [66].…”

Gene promoter methylation signature predicts survival of head and neck squamous cell carcinoma patients

“…An association between CIMP and poor prognosis was also reported for patients with oral cancer, though CIMP was not an independent factor in predicting prognosis. 42 It might be worth addressing a potential link between the MS or MMSS with CIMP in larger cohorts of HNSCC patients for which genome-wide methylation data are available.…”