Integrated Laboratory Systems Inc, Research Triangle Park, NC 27709, USA.
Mutat Res. 2009 Nov 2;670(1-2):96-8. doi: 10.1016/j.mrfmmm.2009.06.011. Epub 2009 Jul 1.
The colorectal cancer paradigm explains how genetic and histological changes lead normal epithelial cell to transform into pre-malignant adenomas then progress to malignant carcinomas. Using the Genetic Alterations in Cancer Knowledge System intragenic allele loss and gene mutation data from approximately 9000 colorectal tumors were compared to the model of colorectal tumor development. The distribution of mutations along the TP53 codons as a function of tumorigenesis also was analyzed. Alterations of APC, KRAS and TP53 were observed in a higher percentage of adenocarcinomas compared to adenomas (P<0.05) indicating that the alterations accumulated with malignancy. Alterations in BRAF, CTNNB, HRAS and NRAS were infrequent regardless of morphology. Differences were observed in the distribution of TP53 mutations with tumorigenesis. Mutations (single base substitutions) occurred most frequently at codons 175 and 273 in both tumor types; however, in adenocarcinomas the mutation incidence at codon 248 was approximately three times that reported in adenomas. It is proposed that the higher incidence of mutation at codon 248 is a later event in colorectal tumorigenesis that occurs as the tumors become malignant.
结直肠癌发生模式解释了遗传和组织学变化如何导致正常上皮细胞转化为癌前腺瘤，然后进展为恶性癌。使用癌症知识系统中的遗传改变，比较了大约 9000 个结直肠肿瘤的基因内等位基因缺失和基因突变数据与结直肠肿瘤发生发展的模型。还分析了 TP53 密码子中突变与肿瘤发生的关系。与腺瘤相比，腺癌中 APC、KRAS 和 TP53 的改变更为常见（P<0.05），表明随着恶性程度的增加，这些改变逐渐积累。BRAF、CTNNB、HRAS 和 NRAS 的改变无论形态如何都很少见。TP53 突变的分布随肿瘤发生而变化。在这两种肿瘤类型中，突变（单碱基取代）最常发生在密码子 175 和 273；然而，在腺癌中，密码子 248 的突变发生率大约是腺瘤的三倍。因此，提出密码子 248 的突变发生率较高是结直肠肿瘤发生的一个后期事件，随着肿瘤变得恶性而发生。
