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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Carcinogens induce genome-wide loss of heterozygosity in normal stem cells without persistent chromosomal instability
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Carcinogens induce genome-wide loss of heterozygosity in normal stem cells without persistent chromosomal instability

机译：致癌物诱导正常干细胞中全基因组杂合性丧失，而没有持续的染色体不稳定

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摘要

Widespread losses of heterozygosity (LOH) in human cancer have been thought to result from chromosomal instability caused by mutations affecting DNA repair/genome maintenance. However, the origin of LOH in most tumors is unknown. The present study examined the ability of carcinogenic agents to induce LOH at 53 sites throughout the genome of normal diploid mouse ES cells. Brief exposures to nontoxic levels of methylnitrosourea, diepoxybutane, mitomycin C, hydroxyurea, doxorubicin, and UV light stimulated LOH at all loci at frequencies ranging from 1-8 x 10(-3) per cell (10-123 times higher than in untreated cells). This greatly exceeds the frequencies at which these agents have been reported to induce point mutations and is comparable to the rates of LOH observed in ES cells lacking the gene responsible for Bloom syndrome, an inherited DNA repair defect that results in greatly increased risk of cancer. These results suggest that LOH contributes significantly to the carcinogenicity of a variety of mutagens and raises the possibility that genome-wide LOH observed in some human cancers may reflect prior exposure to genotoxic agents rather than a state of chromosomal instability during the carcinogenic process. Finally, as a practical matter, chemically induced LOH is expected to enhance the recovery of homozygous recessive mutants from phenotype-based genetic screens in mammalian cells.
机译：人们普遍认为，人类癌症中杂合性（LOH）的广泛丧失是由于影响DNA修复/基因组维持的突变引起的染色体不稳定性所致。然而，LOH在大多数肿瘤中的起源尚不清楚。本研究检查了致癌剂在正常二倍体小鼠ES细胞基因组中53个位点诱导LOH的能力。短暂暴露于无毒水平的甲基亚硝基脲，二环氧丁烷，丝裂霉素C，羟基脲，阿霉素和紫外线在所有位点刺激LOH，频率为每个细胞1-8 x 10（-3）（比未处理的细胞高10-123倍） ）。这大大超过了报道这些试剂诱导点突变的频率，并且与缺乏引起Bloom综合征的基因的ES细胞中观察到的LOH发生率相当，后者是导致遗传风险大大增加的遗传DNA修复缺陷。这些结果表明，LOH显着促进了多种诱变剂的致癌性，并增加了在某些人类癌症中观察到的全基因组LOH可能反映了先前暴露于遗传毒性剂而不是致癌过程中染色体不稳定状态的可能性。最后，实际上，化学诱导的LOH有望增强哺乳动物细胞中基于表型的遗传筛选中纯合隐性突变体的恢复。

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