Parker A R, Leonard C P, Hua L, Francis R O, Dhara S, Maitra A, Eshleman J R
Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA.
Br J Cancer. 2004 Apr 19;90(8):1666-71. doi: 10.1038/sj.bjc.6601740.
An early step in the carcinogenesis of hereditary non-polyposis colorectal cancer (HNPCC) and some sporadic colorectal cancers (CRCs) is the acquisition of a 'mutator phenotype' resulting from defects in DNA mismatch repair (MMR) genes, which normally maintain genomic stability. This mutator phenotype causes an approximately 100-1000-fold increase in base substitutions and small insertion/deletion mutations thereby driving carcinogenesis. It also causes genome-wide microsatellite instability (MSI) due to the inability to repair mutations within these small, hard to replicate, repetitive DNA elements. In contrast, less is known about the role of mutator phenotypes in microsatellite stable (MSS) CRC. In this report, we have measured the mutation rates in 11 MSS CRC cell lines to obtain an estimate of the prevalence of mutator phenotypes in MSS carcinogenesis. Of the 11 cell lines, three of them (27%) possess spontaneous hypoxanthine phosphoribosyltransferase mutation rates approximately 10-100-fold above background. When challenged with alkylating and oxidising agents, the degree of survival and apoptotic responses are different, indicating that these cell lines may represent more than one mutator phenotype. These data demonstrate that a significant portion of MSS CRC cell lines has increased mutation rates and that this may play a role in MSS CRC carcinogenesis.
遗传性非息肉病性结直肠癌（HNPCC）及部分散发性结直肠癌（CRC）致癌过程的早期步骤是获得一种“突变体表型”，这是由DNA错配修复（MMR）基因缺陷导致的，而MMR基因通常维持基因组稳定性。这种突变体表型会使碱基置换及小的插入/缺失突变增加约100 - 1000倍，从而推动致癌进程。由于无法修复这些小的、难以复制的重复性DNA元件中的突变，它还会导致全基因组微卫星不稳定性（MSI）。相比之下，关于突变体表型在微卫星稳定（MSS）CRC中的作用了解较少。在本报告中，我们测量了11个MSS CRC细胞系中的突变率，以估计突变体表型在MSS致癌过程中的发生率。在这11个细胞系中，其中三个（27%）的次黄嘌呤磷酸核糖转移酶自发突变率比背景水平高约10 - 100倍。当受到烷化剂和氧化剂攻击时，其存活程度和凋亡反应有所不同，表明这些细胞系可能代表不止一种突变体表型。这些数据表明，相当一部分MSS CRC细胞系的突变率有所增加，这可能在MSS CRC致癌过程中发挥作用。
