Kakiuchi H, Watanabe M, Ushijima T, Toyota M, Imai K, Weisburger J H, Sugimura T, Nagao M
Carcinogenesis Division, National Cancer Center Research Institute, Tokyo, Japan.
Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):910-4. doi: 10.1073/pnas.92.3.910.
The APC gene plays a major role in human colon carcinogenesis. We determined the genomic structure of the rat Apc gene, and we analyzed mutations in colon tumors induced in F344 rats by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), potent carcinogens contained in ordinary daily human food. Of eight PhIP-induced tumors, one tumor had two Apc mutations, two tumors had a mutation with loss of the normal allele, and one had a mutation. Two of the above five mutations were at nucleotide 1903, one at 2605, and two at 4237, all being a deletion of a guanine base at the 5'-GGGA-3' site and resulting in truncation of the APC protein. Of 13 IQ-induced tumors, 2 had an Apc mutation with loss of the normal allele. The two mutations were a missense mutation (T-->C) at nucleotide 1567 and a nonsense mutation (C-->T) at 2761. Alteration of the Apc gene was shown to play a more important role in PhIP-induced than in IQ-induced rat colon carcinogenesis. PhIP-induced tumors are characterized by their specific and unique mutation, which may be useful for mutational fingerprinting of human cancers.
APC基因在人类结肠癌发生过程中起主要作用。我们确定了大鼠Apc基因的基因组结构，并分析了普通日常人类食物中所含的强效致癌物2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）和2-氨基-3-甲基咪唑并[4,5-f]喹啉（IQ）诱导的F344大鼠结肠肿瘤中的突变。在8个由PhIP诱导的肿瘤中，1个肿瘤有两个Apc突变，2个肿瘤有一个突变且正常等位基因缺失，1个有一个突变。上述5个突变中，2个位于核苷酸1903，1个位于2605，2个位于4237，均为5'-GGGA-3'位点的鸟嘌呤碱基缺失，导致APC蛋白截短。在13个由IQ诱导的肿瘤中，2个有Apc突变且正常等位基因缺失。这两个突变分别是核苷酸1567处的错义突变（T→C）和2761处的无义突变（C→T）。结果表明，Apc基因的改变在PhIP诱导的大鼠结肠癌发生中比在IQ诱导的过程中起更重要的作用。PhIP诱导的肿瘤具有其特定且独特的突变特征，这可能对人类癌症的突变指纹识别有用。
