A Minimal DNA Methylation Signature in Oral Tongue Squamous Cell Carcinoma Links Altered Methylation with Tumor Attributes.
Oral tongue squamous cell carcinomas (OTSCC) 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. In addition, 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-methylcytosine signature identified genes near 16 different differentially methylated regions, which were validated using genomic data from The Cancer Genome Atlas cohort. In our cohort, hypermethylation of MIR10B 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 epidemiologic parameters.



This study reveals a functional minimal methylation profile in oral tongue tumors with associated risk habits, clinical, and epidemiologic outcomes. In addition, NR4A3 downregulation 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). Mol Cancer Res; 14(9); 805-19. ©2016 AACR.
Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, India.
Neeraja M
NM
Krishnan
Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, India.
Kunal
K
Dhas
Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, India.
Jayalakshmi
J
Nair
Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, India.
Vinayak
V
Palve
Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, India.
Jamir
J
Bagwan
Integrated Head and Neck Oncology Program, Mazumdar Shaw Centre for Translational Research, Bangalore, India.
Gangotri
G
Siddappa
Integrated Head and Neck Oncology Program, Mazumdar Shaw Centre for Translational Research, Bangalore, India.
Amritha
A
Suresh
Head and Neck Oncology, Mazumdar Shaw Medical Centre, Bangalore, India.
Vikram D
VD
Kekatpure
Integrated Head and Neck Oncology Program, Mazumdar Shaw Centre for Translational Research, Bangalore, India. Head and Neck Oncology, Mazumdar Shaw Medical Centre, Bangalore, India.
Moni Abraham
MA
Kuriakose
Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, India. Strand Life Sciences, Bangalore, India. binay@ganitlabs.in.
Binay
B
Panda
D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D015536:Down-Regulation; D015870:Gene Expression; D055106:Genome-Wide Association Study; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic; D000077195:Squamous Cell Carcinoma of Head and Neck; D014062:Tongue Neoplasms / Q000235:genetics* / Q000473:pathology