Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
Sci Rep. 2018 Nov 8;8(1):16523. doi: 10.1038/s41598-018-34580-8.
Many anticancer drugs are genotoxic agents inducing DNA breaks in actively proliferating cancer cells. However, these same drugs also induce mutations, mostly genome structural variations (GSVs). The detection of GSVs in normal cells and tissues is a major challenge due to the very low abundance of these mutations, which are essentially only detectable in clonal outgrowths, such as tumors. Previously we developed Structural Variant Search (SVS) - an NGS-based assay for the quantitative detection of somatic GSVs in normal cells. Using an improved version of SVS we now demonstrate that the same dose of the anti-cancer drug bleomycin induces about 5 times more somatic GSVs in quiescent primary human fibroblasts than in proliferating cells. GVS induction in non-dividing, normal cells was subsequently confirmed in vivo by demonstrating that a single dose of bleomycin leads to a significant increase of GSV frequency in mouse liver and heart, two postmitotic tissues. Our findings suggest that normal non-cycling differentiated cells may serve as a reservoir of iatrogenically induced mutations. These results provide more insight into the possible molecular mechanisms that underlie late-life morbidities in cancer survivors exposed to chemotherapy.
许多抗癌药物是诱导 DNA 断裂的遗传毒性药物，主要作用于增殖活跃的癌细胞。然而，这些药物同样也会诱导突变，主要是基因组结构变异（GSV）。由于这些突变的丰度非常低，在正常细胞和组织中检测 GSV 是一个主要的挑战，它们基本上只能在克隆性生长中检测到，如肿瘤。我们之前开发了结构变异搜索（SVS）-一种基于 NGS 的用于检测正常细胞中体细胞 GSV 的定量检测方法。我们使用改进的 SVS 版本，现在证明相同剂量的抗癌药物博莱霉素在静止的原代人成纤维细胞中诱导的体细胞 GSV 比增殖细胞多约 5 倍。非分裂的正常细胞中的 GSV 诱导随后在体内得到了证实，证明单次博莱霉素给药会导致小鼠肝脏和心脏（两个有丝分裂后的组织）中 GSV 频率显著增加。我们的发现表明，正常的非循环分化细胞可能是医源性诱导突变的储存库。这些结果为了解接受化疗的癌症幸存者晚年出现病态的可能分子机制提供了更多的见解。
