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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.