Elucidation, of the interacting mechanism between epigenetic and genetic alterations in gastrointestinal cancers and of the possible application to the clinic

我们已经研究了胃肠道癌变和肿瘤进展的分子机制。我们已经确定了几个突变在癌变中起重要作用的基因，包括结直肠癌和胃癌中的E2F-4和食管鳞状细胞癌中的ING1。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）。我们最近的大部分工作都集中在胃肠道癌症中多个基因的启动子甲基化上，我们在这个领域取得了巨大的进展。我们发现重要的DNA修复基因MGMT （06-methylguanine DNA methyltransferase）的表达受促子甲基化控制，并且甲基化水平与结直肠癌的预后和化疗耐药密切相关（Clinical Cancer Research）。此外，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。此外，我们发现异常DNA甲基化仅是老年MSI-H患者的一种疾病，但与Lynch综合征的一个子集相关。在此，我们发现各种表观遗传标记的甲基化不是随机现象，而是与KRAS和/或BRAF突变明显分离。因此，RAS-RAF通路的整体激活与散发性和遗传性结肠癌的异常DNA甲基化有关。我们还研究了microRNA在胃肠道癌变中可能的表观遗传作用。少

We have been studied molecular mechanisms of gastrointestinal carcinogenesis and 'cancer progression. We have been identified several genes whose mutation has a important role in carcinogenesis, including E2F-4 in colorectal and gastric cancer and ING1 in esophageal squamous cell cancer. 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). Most of our recent work was focused on this promoter methylation of multiple genes in gastrointestinal cancers, and we made tremendous, progress in this' field. We found that the important DNA repair gene MGMT (06-methylguanine DNA methyltransferase) is controlled of its expression by promo … More ter methylation, and the level of methylation is strongly related to the prognosis and chemoresistance of colorectal cancers (Clinical Cancer Research). Furthermore, 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. In addition, we found that aberrant DNA methylation is only a disease of older individuals with MSI-H but in associated with a subset of Lynch syndrome. Herein, we found that methylation of various epigenetic markers is not a random phenomenon but is clearly segregated with both KRAS and/or BRAF mutations. Thus, overall activation of RAS-RAF pathway associates with aberrant DNA methylation in both sporadic and hereditary colon cancers. We also investigate microRNA as a possible epigenetic role in gastrointestinal carcinogenesis. Less