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

AbstractOral
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).