Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, India.
Integrated Head and Neck Oncology Program, Mazumdar Shaw Centre for Translational Research, Bangalore, India.
Mol Cancer Res. 2016 Sep;14(9):805-19. doi: 10.1158/1541-7786.MCR-15-0395. Epub 2016 Jun 10.
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.
口腔舌鳞状细胞癌（OTSCC）是头颈部具有侵袭性的同质肿瘤群，早期向淋巴结转移，区域复发率较高。此外，口腔舌癌在年轻人群中的发病率呈上升趋势。研究与改变的基因表达相关的功能性 DNA 甲基化变化对于理解肿瘤发生和转移的机制至关重要。此类研究还为口腔舌鳞癌中与病毒感染、肿瘤转移和患者生存相关的生物标志物提供了重要的见解。因此，我们对肿瘤（N=52）进行了全基因组甲基化分析，并将改变的甲基化与差异基因表达相关联。鉴定出 16 个不同的甲基化区域附近的肿瘤特异性 DNA 5-甲基胞嘧啶最小签名基因，这些基因使用来自癌症基因组图谱队列的基因组数据进行了验证。在我们的队列中，MIR10B 的高甲基化与其靶基因 NR4A3 和 BCL2L11 的差异表达显著相关（P=0.0125 和 P=0.014），这与患者的无病生存率呈负相关（P=9E-15 和 P=2E-15）。最后，发现 FUT3、TRIM5、TSPAN7、MAP3K8、RPS6KA2、SLC9A9 和 NPAS3 基因的差异甲基化与某些临床和流行病学参数相关。
本研究揭示了口腔舌肿瘤中具有相关风险习惯、临床和流行病学结果的功能性最小甲基化谱。此外，NR4A3 的下调及其与患者生存的相关性提示口腔舌肿瘤的潜在治疗靶点。本研究的数据已存入 NCBI Geo 数据库（注册号 GSE75540）。 Mol Cancer Res; 14(9); 805-19. ©2016 AACR.
