结直肠癌中DNA甲基化与SNP热点相关性研究

项目名称： 结直肠癌中DNA甲基化与SNP热点相关性研究

项目编号： No.81502443

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 邵娇芳

作者单位： 南京医科大学

项目金额： 18万元

中文摘要： 结直肠癌是一种死亡率极高的恶性肿瘤，是研究基因组与表观遗传组的重要模型。基因组不稳定性指的是基因组的遗传改变，可在单碱基、微卫星和染色体水平观测到，是肿瘤的重要标记，受表观遗传组的影响。已有研究发现组蛋白修饰、CpG含量与SNP密度具有较高的相关性，但目前仍不清楚影响癌症基因组中SNP密度的因素。本项目旨在通过分析多组结直肠癌来源的基因组测序、DNA甲基化测序、DNase-Seq、ChIP-Seq等多种类型的数据，运用相关性计算、聚类分析、多元回归建模等方法，探索SNP热点区域与DNA甲基化水平、DNA酶Ⅰ超敏感区、CTCF结合、RNA POLⅡ结合之间的关系，并在小规模病人组织样本中验证关键SNP区域，为结直肠癌的诊断及预后提供候选的标记物。本研究主要利用大数据研究基因组与表观组之间的相互作用，探索癌症基因组不稳定形成的机制，可为今后的肿瘤治疗提供方向。

中文关键词： C08_结；直肠肿瘤；SNP热点；DNA甲基化；DNA酶Ⅰ超敏感区

英文摘要： Colorectal cancer (CRC), the third leading cause of worldwide cancer-related deaths in men and women, is developed by a series of steps involved accumulation of mutations, and considered as a classic model for genetic basics for tumorigenesis. Genomic instability is a hallmark of cancer, and can occur at nucleotide, microsatellite, or chromosomal level. It is still unclear how the instability arises during the cancer development, or how it relates to other factors. It has been shown that genome will interplay with epigenome and promote oncogenic transformation together. Previous researches have found that histone modification and CpG content are associated with single nucleotide polymorphisms (SNP) density. In this study, genome sequencing data will be analyzed to investigate whether there are any SNP hotspots in CRC. Meanwhile, bisulfite sequencing, DNase-Seq and ChIP-Seq data from CRC cell lines and tissues will be analyzed. By clustering, correlation test and linear modeling using the large scale datasets, the association of DNA methylation level, DNase I hypersensitive sites (DHS), CTCF binding and RNA POLⅡbinding with SNP hotspots will be evaluated. The key SNP hotspots with strong association to DNA methylation or the tested regulatory regions will then be validated in CRC tissues by Sanger sequencing technology. Also, survival test will be performed to exam whether the candidate sites are associated with CRC patients' survival time using TCGA datasets. This study attempts to discover the SNP hotspots in CRC and explain the phenomena using DNA methylation and DHS data. The key hotspots can provide potential diagnosis and prognosis biomarker for CRC. In summary, the research is designed to find whether epigenome can affect the genomic instability at single nucleic acid level, providing novel strategy for CRC diagnosis and treatment.

英文关键词： colorectal cancer;SNP hotspots;DNA methylation;DNase I hypersensitive sites