A Minimal DNA Methylation Signature in Oral Tongue Squamous Cell Carcinoma Links Altered Methylation with Tumor Attributes.

Abstract

Oral tongue squamous cell carcinomas (OTSCCs) are a homogenous group of aggressive tumors in the head and neck region that spread early to lymph nodes and have a higher incidence of regional failure. Additionally, there is a rising incidence of oral tongue cancer in younger populations. Studies on functional DNA methylation changes linked with altered gene expression are critical for understanding the mechanisms underlying tumor development and metastasis. Such studies also provide important insight into biomarkers linked with viral infection, tumor metastasis and patient survival in OTSCC. Therefore, we performed genome-wide methylation analysis of tumors (N = 52) and correlated altered methylation with differential gene expression. The minimal tumor-specific DNA 5-methycytosine (5mc) signature identified genes near 16 different differentially methylated regions (DMRs), which were validated using genomic data from The Cancer Genome Atlas (TCGA) cohort. In our cohort, hypermethylation of miR-10b was significantly associated with the differential expression of its target genes NR4A3 and BCL2L11 (P = 0.0125 and P = 0.014 respectively), which was inversely correlated with disease-free survival (P = 9E-15 and P = 2E-15 respectively) in patients. Finally, differential methylation in FUT3, TRIM5, TSPAN7, MAP3K8, RPS6KA2, SLC9A9 and NPAS3 genes was found to be predictive of certain clinical and epidemiological parameters.

IMPLICATIONS:
This study reveals a functional minimal methylation profile in oral tongue tumors with associated risk habits, clinical and epidemiological outcomes. In addition, NR4A3 down-regulation and correlation with patient survival suggests a potential target for therapeutic intervention in oral tongue tumors. Data from the current study are deposited in the NCBI Geo database (Accession number GSE75540).