Abstract
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.
Highlights
Advances in early cancer diagnosis and treatment strategies have resulted in over 14 million cancer survivors in the United States[1]
It is conceivable that chemotherapy will accelerate the normal age-associated accumulation of genome structural variants (GSVs) in tissues[12,13], offering one possible explanation for the multiple late-life morbidities, including secondary malignancies and early onset of symptoms typically associated with aging, in cancer survivors treated with chemotherapy[14,15,16]
To improve accuracy of GSV calling in Structural Variant Search (SVS) we have designed a Ligation-mediated Chimera-Free (LCF) sequencing library preparation protocol (Fig. 1A)
Summary
Advances in early cancer diagnosis and treatment strategies have resulted in over 14 million cancer survivors in the United States[1]. We developed Structural Variant Search (SVS) – a novel next-generation sequencing (NGS)-based analytical tool for the quantitative detection of somatic GSVs18 This assay utilizes ultra-low coverage sequencing data and allows accurate genome-wide assessment of frequency and spectra of low-abundant GSVs induced by bleomycin, a cancer therapeutic agent. Product size (bp) 9931 9882 9984 10350 10385 significantly more susceptible to the mutagenic effects of chemotherapeutic drug bleomycin than proliferating cells and further demonstrate that GSVs are induced in vivo in postmitotic tissues of mice treated with the drug. These results shed light on a possible mechanism of late-life effects of cancer chemotherapy
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