Levy D B, Smith K J, Beazer-Barclay Y, Hamilton S R, Vogelstein B, Kinzler K W
Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231.
Cancer Res. 1994 Nov 15;54(22):5953-8.
Germline mutations of the adenomatous polyposis coli (APC) gene lead to multiple intestinal tumors in familial adenomatous polyposis patients and in multiple intestinal neoplasia (Min) mice. Current models predict that inactivation of the remaining normal allele of a tumor suppressor gene is rate limiting for tumor formation, but this has been difficult to prove. While examination of colorectal adenomas from familial adenomatous polyposis patients identified somatic inactivating mutations of the second allele in the majority of tumors (19 of 24), the absolute requirement for an early inactivating event could not be demonstrated. In contrast, inactivation of the remaining allele of the murine APC (Apc) could be demonstrated in 100% (30 of 30) of tumors from Min mice. Moreover, inactivation was observed in the earliest recognizable phase of tumors, including some lesions containing as few as two dysplastic crypts. These results suggest that the mutation of the second APC allele is an early event in Min and familial adenomatous polyposis tumorigenesis, supporting Knudson's hypothesis.
腺瘤性结肠息肉病（APC）基因的种系突变会导致家族性腺瘤性息肉病患者和多发性肠道肿瘤（Min）小鼠出现多发性肠道肿瘤。目前的模型预测，肿瘤抑制基因剩余正常等位基因的失活是肿瘤形成的限速步骤，但这一点很难得到证实。虽然对家族性腺瘤性息肉病患者的结肠腺瘤进行检查时发现，大多数肿瘤（24个中有19个）的第二个等位基因存在体细胞失活突变，但早期失活事件的绝对必要性却无法得到证明。相比之下，在Min小鼠的100%（30个中有30个）肿瘤中都能证明小鼠APC（Apc）剩余等位基因的失活。此外，在肿瘤最早可识别阶段就观察到了失活现象，包括一些仅有两个发育异常隐窝的病变。这些结果表明，第二个APC等位基因的突变是Min和家族性腺瘤性息肉病肿瘤发生过程中的早期事件，支持了克努森假说。
