Microsatellite instability and aberrant methylation in gastrointestinal cancer and its application to molecular target therapy

DNA错配修复基因缺陷引起的微卫星不稳定性（Microsatellite instability， MSI）在遗传性非息肉病性结直肠癌（HNPCC）中起重要作用。MSI在散发性结直肠癌和胃癌中也起作用。在目前的研究中，我们确定了胃肠道癌症中MSI和/或异常甲基化失活的基因，并研究了它们在胃肠道癌症发生和进展中的作用。DNA甲基化是一种表观遗传变化，可以通过甲基转移酶抑制剂逆转。我们检查了导致胃肠道癌症分子靶向治疗发展的基础研究。我们研究了胃肠道癌症中MSI和甲基化变化之间的关系。我们发现80%伴有MSI的散发性结直肠癌是由与CpG岛甲基化表型（CIMP）相关的hMLH1的表观遗传失活引起的。CIMP阳性结直肠癌表现出明显的遗传和表观遗传特征，包括p16甲基化和BRAF突变频率高，p53突变频率低。这些结果表明，与HNPCC相比，CIMP阳性结直肠癌的发生途径不同。我们还发现WNT和Ras调节因子的表观遗传失活在WNT和Ras信号通路的激活中起作用。甲基转移酶抑制剂对DNA甲基化的抑制导致促凋亡基因的诱导，从而导致癌细胞凋亡的增强。我们的研究结果表明，DNA甲基化可以成为治疗胃肠道癌症的分子靶点。

Microsatellite instability (MSI) caused by the defect of DNA mismatch repair genes plays a role in Hereditary non-polyposis colorectal cancer (HNPCC). MSI also plays a role in sporadic colorectal and gastric cancers. In the current study, we identified the genes inactivated by MSI and/or aberrant methylation in gastrointestinal cancers, and examined their role in development and progression of gastrointestinal cancers. DNA methylation is an epigenetic change that can be reversed by methyltransferase inhibitors. We examine basic research that leads to development of molecular target therapy in gastrointestinal cancers. We examined the relationship between MSI and methylation changes in gastrointestinal cancers. We found that 80% of sporadic colorectal cancers with MSI were caused by epigenetic inactivation of hMLH1 associated with CpG island methylator phenotype (CIMP). CIMP positive colorectal cancers showed distinct genetic and epigenetic features including high frequency of methylation of p16 and mutations of BRAF, and low frequency of p53 mutations. These results indicated that CIMP positive colorectal cancer arises in a different pathway compared to HNPCC. We also showed that epigenetic inactivation of the regulators of WNT and Ras play a role in activation of WNT and Ras signaling pathways. Inhibition of DNA methylation by a methyltransferase inhibitor results in induction of pro-apoptotic genes, which results in enhancement of apoptosis in cancer cells. Our results indicated that DNA methylation can be a molecular target for therapy of gastrointestinal cancers.