Development of high sensitive screening method by fecal DNA test targeting colorectal cancer; pancreatic and binary tract cancers

我们已经研究了胃肠道癌发生和癌症进展的分子机制。近年来，许多类型的癌变不仅涉及基因，包括突变和缺失，而且涉及表观遗传改变。最典型的表观遗传改变是启动子超甲基化，导致基因沉默。DNA甲基化优先发生在被称为CpG岛的密集CpG位点集群中。因此，参考CpG岛甲基化表型（CIMP）。我们通过KRAS和BRAF的突变状态对结直肠癌进行分类，并发现与结直肠癌中多启动子甲基化的甲基化状态密切相关（Journal of Clinical Oncology）。最近，我们研究了RAS-RAF信号通路的激活与大量甲基化标记（包括cimp相关和不相关的位点）的整体高甲基化之间的总体关系。有趣的是，我们发现异常DNA甲基化只是老年MSI-H患者的一种疾病，但与所有结直肠癌亚群相关。在此，我们发现如果我们选择正确的甲基化标记，表观遗传标记可以用于结直肠癌的筛查。我们还开发了一种新的方法来检测粪便中癌症脱落DNA中的癌症衍生甲基化，并申请了几项专利。我们也关注主要因筛查和早期诊断困难而预后较差的癌症，如胰腺癌和肝胆道癌。

We have been studied molecular mechanisms of gastrointestinal carcinogenesis and cancer progression. Recently not only genetic, including mutations and deletions, but also epigenetic alterations are involved in many types of carcinogenesis. The most typical epigenetic alteration is the promoter hypermethylation, which causes the silencing of the gene. DNA methylation occurs preferentially within dense clusters of CpG sites know as CpG islands. Therefore reference is made to a CpG island methylator phenotype (CIMP). we classified colorectal cancer by mutational status of KRAS and BRAF, and showed close correlation to the methylation status of the multiple promoter methylation in colorectal cancer (Journal of Clinical Oncology). More recently, we investigated the overall relationship between activation of RAS-RAF signaling pathway and global hypermethylation in a large panel of methylation markers that included both CIMP-related and unrelated loci. Interestingly, we found that aberrant DNA methylation is only a disease of older individuals with MSI-H but in associated with all subsets of colorectal cancers. Herein, we found that epigenetic markers can be used for the screening of colorectal cancer if we chose the correct methylation marker. We also developed a novel method to detect cancer-derived methylation in the exfoliated DNA from cancer in feces and applied several patents. We have also focused on the cancer with poor prognosis mainly due to the difficulty in screening and early diagnosis, such as pancreatic and hepato-biliary tract cancers.