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癌症进展的分子机制。我们已经确定了几个突变在肿瘤发生中起重要作用的基因，包括在结直肠癌和胃癌中的E2F-4和在食道鳞状细胞癌中的ING1。目前，不仅遗传，包括突变和缺失，而且表观遗传改变也参与了许多类型的癌症发生。最典型的表观遗传学改变是启动子的超甲基化，导致基因沉默。DNA甲基化优先发生在密集的CpG位点簇中，称为CpG岛。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，我们在这一领域取得了巨大的进展。我们发现，重要的dna修复基因mgmt(06-甲基鸟嘌呤dna甲基转移酶)的表达受…启动子的调控。更多的甲基化，甲基化水平与结直肠癌的预后和化疗耐药性密切相关(临床癌症研究)。此外，我们根据KRAS和BRAF的突变状态对结直肠癌进行分类，并显示与结直肠癌多启动子甲基化状态密切相关(《临床肿瘤学杂志》)。最近，我们在包括CIMP相关和无关基因在内的一大组甲基化标记中研究了RAS-RAF信号通路的激活和全球高甲基化之间的总体关系。此外，我们发现DNA甲基化异常只是患有MSI-H的老年患者的一种疾病，但与Lynch综合征的子集有关。在这里，我们发现各种表观遗传标记的甲基化不是一个随机现象，而是明显地与KRAS和/或BRAF突变分离。因此，在散发性和遗传性结肠癌中，RAS-RAF通路的全面激活与DNA甲基化的异常有关。我们还研究了microRNA在胃肠道肿瘤发生中可能的表观遗传学作用。较少

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