Data_Sheet_1_Whole Genome DNA Methylation and Gene Expression Profiling of Oropharyngeal Cancer Patients in North-Eastern India: Identification of Epigenetically Altered Gene Expression Reveals Potential Biomarkers.docx

Oropharyngeal cancer is a subtype of head and neck squamous cell carcinoma that is associated with unique risk exposures like consumption of smokeless tobacco and areca nut and is highly prevalent in the northeastern region of India, especially Meghalaya. However, the underlying epigenetic and transcriptomic changes in this cancer type is yet to be delineated. We have undertaken a study on genome wide somatic alterations in the DNA methylation and transcriptome in oropharyngeal cancer patients from this region using genome wide techniques in paired tumors and adjacent normal tissues. By using integrative approaches, we have identified 194 epigenetically silenced and 241 epigenetically overexpressed genes in the tumor tissue of these patients. Pathways that are significantly enriched by these genes include the pathways of immune systems, such as the interleukin signaling pathways and Toll-like receptor signaling pathway. Also, osteoclast differentiation pathway was found to be epigenetically upregulated. The pathways enriched by the epigenetically downregulated genes were found to be predominantly those involved in xenobiotic metabolism and keratinization. Two major transcription factors – SPI1 and RUNX1 were identified as epigenetically dysregulated, which further modulates 129 downstream genes. Comparison of our observations with the head and neck cancer data from TCGA revealed distinct DNA methylation and gene expression landscapes which might be specific for oropharyngeal cancer. HPV DNA sequences were not detected in any of the tumor samples in RNA-Seq data. The results obtained in this study might provide improved understanding of the disease.

口咽癌（Oropharyngeal cancer）是头颈部鳞状细胞癌（head and neck squamous cell carcinoma）的一个亚型，其相关独特风险暴露包括无烟烟草与槟榔（areca nut）的摄入，且在印度东北部地区，尤其是梅加拉亚邦（Meghalaya），患病率极高。然而，该癌种潜在的表观遗传与转录组变化尚未被阐明。本研究针对该地区的口咽癌患者，利用全基因组技术对其配对肿瘤组织与邻近正常组织的DNA甲基化及转录组中的全基因组体细胞变异展开分析。通过整合分析方法，我们在这些患者的肿瘤组织中鉴定出194个表观遗传沉默基因与241个表观遗传过表达基因。上述基因显著富集的通路涵盖免疫系统相关通路，例如白细胞介素信号通路与Toll样受体（Toll-like receptor）信号通路。此外，破骨细胞分化通路被发现存在表观遗传上调。而表观遗传下调基因所富集的通路则主要涉及异生物质代谢与角质化过程。两种核心转录因子——SPI1与RUNX1被鉴定为存在表观遗传失调，它们可进一步调控129个下游基因。将本研究的观测结果与癌症基因组图谱（The Cancer Genome Atlas, TCGA）中的头颈部癌数据进行对比后发现，二者的DNA甲基化与基因表达谱存在显著差异，这一特征或为口咽癌所特有。在所有肿瘤样本的RNA测序（RNA-Seq）数据中，均未检测到人乳头瘤病毒（Human Papillomavirus, HPV）的DNA序列。本研究所得结果或可加深人们对该疾病的认知。