Malkhosyan S, McCarty A, Sawai H, Perucho M
La Jolla Cancer Reaearch Foundation, California 92037, USA.
Mutat Res. 1996 May;316(5-6):249-59. doi: 10.1016/s0921-8734(96)90007-7.
We have determined the frequency and spectrum of spontaneous mutations at the hprt locus in LoVo, HCT116, LS180 and DLD-1 colon carcinoma cell lines exhibiting microsatellite genetic instability. Each cell line has a different mutator gene. LoVo and HCT116 cells have mutated hMSH2 and hMLH1 genes, respectively, which account for the majority of hereditary non-polyposis colorectal cancer (HNPCC). LS180 cells are wild type for these genes and also for hPMS1 and hPMS2 mismatch repair genes. DLD-1 cells harbor a mutated GTBP mismatch binding factor and a mutated DNA Polymerase delta. The mutation rate at the hprt locus was several hundred fold higher in these cell lines relative to control cell lines without microsatellite instability. The mutations were frameshifts (deletions and insertions of a single nucleotide in short repeats) and single base substitutions (transversions and transitions). Some mutations were shared by these four cell lines. However, every cell line also exhibited a distinctive spectrum of mutations suggesting that each mutator gene induces a particular mutator phenotype. These results also suggest that the frequency and spectrum of somatic mutations in tumor cells of the microsatellite mutator phenotype may have diagnostic applications to discriminate among the diverse underlying mutator genes.
我们已经确定了表现出微卫星遗传不稳定性的LoVo、HCT116、LS180和DLD-1结肠癌细胞系中hprt基因座自发突变的频率和谱。每个细胞系都有一个不同的突变基因。LoVo和HCT116细胞分别有突变的hMSH2和hMLH1基因，这两种基因占遗传性非息肉病性结直肠癌（HNPCC）的大部分。LS180细胞对于这些基因以及hPMS1和hPMS2错配修复基因来说是野生型。DLD-1细胞含有一个突变的GTBP错配结合因子和一个突变的DNA聚合酶δ。相对于没有微卫星不稳定性的对照细胞系，这些细胞系中hprt基因座的突变率高出数百倍。这些突变是移码突变（短重复序列中单个核苷酸的缺失和插入）和单碱基替换（颠换和转换）。这四个细胞系有一些共同的突变。然而，每个细胞系也表现出独特的突变谱，这表明每个突变基因诱导一种特定的突变表型。这些结果还表明，微卫星突变体表型的肿瘤细胞中体细胞突变的频率和谱可能在诊断上有应用价值，可用于区分不同的潜在突变基因。
