Esteller M, Sparks A, Toyota M, Sanchez-Cespedes M, Capella G, Peinado M A, Gonzalez S, Tarafa G, Sidransky D, Meltzer S J, Baylin S B, Herman J G
Department of Oncology, The Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.
Cancer Res. 2000 Aug 15;60(16):4366-71.
Germ-line mutations in the tumor suppressor gene APC are associated with hereditary familial adenomatous polyposis (FAP), and somatic mutations are common in sporadic colorectal tumors. We now report that methylation in the promoter region of this gene constitutes an alternative mechanism for gene inactivation in colon and other tumors of the gastrointestinal tract. The APC promoter is hypermethylated in 18% of primary sporadic colorectal carcinomas (n = 108) and adenoma (n = 48), and neoplasia with APC methylation fails to express the APC transcript. Methylation affects only wild-type APC in 95% of cases and is not observed in tumors from FAP patients who have germ-line APC mutations. As with APC mutation, aberrant APC methylation occurs early in colorectal carcinogenesis. When other tumor types are analyzed (n = 208), methylation of the APC promoter is not restricted to the colon but is present in tumors originating elsewhere in the gastrointestinal tract but rarely in other tumors. Our data suggest that hypermethylation of APC provides an important mechanism for impairing APC function and further underscores the importance of the APC pathway in gastrointestinal tumorigenesis.
肿瘤抑制基因APC的种系突变与遗传性家族性腺瘤性息肉病（FAP）相关，而体细胞突变在散发性结直肠癌中很常见。我们现在报告，该基因启动子区域的甲基化构成了结肠和其他胃肠道肿瘤中基因失活的另一种机制。在18%的原发性散发性结直肠癌（n = 108）和腺瘤（n = 48）中，APC启动子发生高甲基化，且发生APC甲基化的肿瘤不表达APC转录本。在95%的病例中，甲基化仅影响野生型APC，而在具有种系APC突变的FAP患者的肿瘤中未观察到甲基化。与APC突变一样，异常的APC甲基化在结直肠癌发生的早期就会出现。当分析其他肿瘤类型（n = 208）时，APC启动子的甲基化并不局限于结肠，而是存在于起源于胃肠道其他部位的肿瘤中，但在其他肿瘤中很少见。我们的数据表明，APC的高甲基化为损害APC功能提供了一种重要机制，并进一步强调了APC通路在胃肠道肿瘤发生中的重要性。
