Bleomycin-induced genome structural variations in normal, non-tumor cells

Area of Science:

• Genomics
• Cancer Biology
• Toxicology

Background:

• Anticancer drugs often cause DNA damage and mutations, primarily genome structural variations (GSVs).
• Detecting low-abundance GSVs in normal cells is challenging, often requiring clonal expansion like in tumors.
• Structural Variant Search (SVS) is an NGS assay for quantifying somatic GSVs in normal cells.

Purpose of the Study:

• To investigate the induction of somatic GSVs by bleomycin in both proliferating and quiescent normal human cells.
• To confirm GSV induction in non-dividing cells in vivo.
• To explore the implications for late-life morbidities in cancer survivors.

Main Methods:

• Utilized an improved version of the Structural Variant Search (SVS) next-generation sequencing (NGS) assay.
• Compared GSV induction by bleomycin in quiescent versus proliferating primary human fibroblasts.
• Administered bleomycin to mice and assessed GSV frequency in liver and heart tissues.

Main Results:

• Bleomycin induced approximately 5 times more somatic GSVs in quiescent fibroblasts compared to proliferating cells.
• A single dose of bleomycin significantly increased GSV frequency in mouse liver and heart, which are postmitotic tissues.
• Demonstrated GSV induction in normal, non-cycling cells both in vitro and in vivo.

Conclusions:

• Normal, non-cycling differentiated cells can accumulate chemotherapy-induced mutations (GSVs).
• These cells may act as a reservoir for iatrogenically induced mutations.
• Findings offer insights into molecular mechanisms of late-life morbidities in chemotherapy-exposed cancer survivors.