Elucidation of new molecular mechanism of cancer caused by gene promoter methylation and its clinical aplication

我们已经研究了胃肠道癌发生和癌症进展的分子机制。我们的研究重点之一是结肠直肠癌，我们发现了重要的转录因子之一E2F4的癌症特异性突变，这是一个与微卫星不稳定表型的结直肠癌进展密切相关的新基因（在cancer Res.发表2篇文章）。我们还发现ING-1在食管鳞状细胞癌中是一个新的重要靶基因（发表于cancer Res.）。我们还研究了结直肠癌早期（刚侵入粘膜下层）发生的分子事件，我们发现在这组癌症中，低频率微卫星（MSI-L）的发生率很高（发表在cancer Res.）。MSI-L在晚期结直肠癌中的发生率确实很低，约为10%，然而，我们在50%的早期结直肠癌中发现了MSI-L表型。现在越来越多的研究人员参与到新的MSI-L致癌途径中来，这被认为是一个人工产物，因此不是一个有意义的现象。近年来，许多类型的癌变不仅与基因（包括突变和缺失）有关，还与表观遗传现象有关。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，我们在这一领域取得了巨大的进展。通过对启动子甲基化精确图谱的分析，我们发现重要的DNA修复基因MGMT （o6 -甲基鸟嘌呤DNA甲基转移酶）的表达受启动子甲基化控制。我们还发现甲基化水平与结直肠癌的预后和化疗耐药密切相关（临床癌症研究）。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）。少

We have been studied molecular mechanisms of gastrointestinal carcinogenesis and cancer progression. One of our research focuses is colorectal cancer, and we have found the cancer specific mutation in E2F4, one of the important transcription factors, as a new gene strongly related to the colorectal cancer progression characterized as microsatellite instability phenotype (published 2 articles in Cancer Res.). We also found ING-1 as a new important target gene in esophageal squamouse cell cancer (published in Cancer Res.). We also studied the molecular events occur in early stages (just invaded into submucosa) of colorectal cancer, and we found high prevalence of microsatellite in low frequency (MSI-L) in this group of cancers (published in Cancer Res. ). Frequency of MSI-L in advanced colorectal cancer is really low around 10%, however, we found MSI-L phenotype in 50% of the early stage colorectal cancers. Now more and more researchers are involved in the new MSI-L carcinogenesis pathwa … More y, which was thought to be an artifact an thus not a meaningful phenomenon.Recently not only genetic, including mutations and deletions, but also epigenetic phenomenon 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 methlator 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 (O6-methylguanine DNA methyltransferase) is controlled of its expression by promoter methylation, by analyzing precise map of methylation in its promoter. We also found that 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). Less