Grady W M, Willis J, Guilford P J, Dunbier A K, Toro T T, Lynch H, Wiesner G, Ferguson K, Eng C, Park J G, Kim S J, Markowitz S
Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio, USA.
Nat Genet. 2000 Sep;26(1):16-7. doi: 10.1038/79120.
Aberrant promoter methylation and the associated loss of gene expression is a common accompaniment of human cancers. Nonetheless, it has been challenging to demonstrate in any given tumour that methylation of a specific gene was causal and not consequent to malignant transformation. In this regard, our attention was drawn to the genesis of gastric cancers in individuals with hereditary diffuse gastric cancer (HDGC). These individuals harbour germline mutations in the gene encoding E-cadherin, CDH1, but their cancers have consistently demonstrated absence of loss of heterozygosity at the CDH1 locus. These findings suggested the hypothesis that CDH1 promoter methylation might function as the 'second genetic hit' in the genesis of these cancers.
异常的启动子甲基化及相关的基因表达缺失是人类癌症的常见伴随现象。然而，要在任何特定肿瘤中证明特定基因的甲基化是致癌原因而非恶性转化的结果一直具有挑战性。在这方面，我们的注意力被吸引到遗传性弥漫性胃癌（HDGC）患者的胃癌发生过程上。这些个体在编码E-钙黏蛋白的基因CDH1中携带种系突变，但他们的癌症始终显示CDH1基因座不存在杂合性缺失。这些发现提示了一个假说，即CDH1启动子甲基化可能在这些癌症的发生中充当“第二次基因打击”。
