MUTATOR PHENOTYPES IN HUMAN COLORECTAL-CARCINOMA CELL-LINES
MUTATOR PHENOTYPES IN HUMAN COLORECTAL-CARCINOMA CELL-LINES
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DOI：
10.1073/pnas.91.14.6319
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发表时间：
1994-07-05
影响因子：
11.1
通讯作者：
MEUTH, M
中科院分区：
文献类型：
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作者：
BHATTACHARYYA, NP;SKANDALIS, A;MEUTH, M
最近的研究表明，遗传性非息肉病性结肠癌患者的肿瘤与微卫星序列的高频改变有关。为了研究这种形式的遗传不稳定性的机制和后果，我们鉴定了三种表达二核苷酸重复不稳定性的结直肠癌细胞系，这些细胞系与遗传性非息肉病重结肠癌肿瘤中发现的二核苷酸重复不稳定性相似，并且在选择性位点上显示出增加的自发突变率。然而，这些细胞系的超突变模式明显不同。在一个品系（HCT116）中，微卫星突变的发生率非常高（每代每个细胞约10-2个突变），而在另外两个品系（DLD-1和HCT15）中，这一发生率相当低。在所有三种肿瘤细胞系中，编码次黄嘌呤鸟嘌呤磷酸核糖基转移酶的位点的突变率都显著升高（200- 600倍），但发生的突变类型不同。HCT116中有24%的次黄嘌呤鸟嘌呤磷酸核糖基转移酶突变是一个特定的移框热点。在DLD-1和HCT15系中，该位点的突变频率显著降低。这些数据表明，结肠直肠癌细胞系中的突变表型可能是突变基因影响不同修复或错误避免途径的结果。
Recent studies have revealed that tumors in patients with hereditary nonpolyposis colon cancer are associated with high frequency alterations of microsatellite sequences. To investigate the mechanisms and consequences of this form of genetic instability, we identified three colorectal carcinoma cell lines that express dinucleotide-repeat instability like that found in hereditary nonpolyposis felon cancer tumors and show increased rates of spontaneous mutation at selectable loci. However, the pattern of hypermutation in these cell lines differed significantly. In one line (HCT116), microsatellite mutations occurred at a remarkably high rate (approximate to 10-2 mutations per cell per generation), whereas this rate was considerably lower in the two other lines (DLD-1 and HCT15). The rate of mutation at the locus encoding hypoxanthine guanine phosphoribosyltransferase was substantially elevated (200- to 600-fold) in all three tumor cell lines, yet the types of mutations arising differed. A specific frame-shift hotspot accounted for 24% of hypoxanthine guanine phosphoribosyltransferase mutations in HCT116. The frequency of mutations at this site was reduced significantly in DLD-1 and HCT15 lines. These data suggest that the mutator phenotypes in the colorectal carcinoma cell lines could be the consequence of mutator genes affecting different repair or error-avoidance pathways.