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#506 Chemotherapy during pregnancy is associated with increased genotoxicity and mutational load in the fetal hematopoietic compartment
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  1. Ilana Struys1,
  2. Carolina Velázquez1,
  3. Joske Ubels2,
  4. Anaïs Van Leeuwen2,
  5. Manosij Ghosh1,
  6. Jarne Geurts1,
  7. Charlotte Lejeune3,
  8. Kristel Van Calsteren3,
  9. Lode Godderis1,
  10. Thierry Voet1,
  11. Ruben Van Boxtel2,
  12. Liesbeth Lenaerts1 and
  13. Frédéric Amant3
  1. 1KU Leuven, Leuven, Belgium
  2. 2Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
  3. 3UZ Leuven, Leuven, Belgium

Abstract

Introduction/Background Prenatal exposure to chemotherapy is shown to not impair the health of children (up to age 9). However, genotoxic chemotherapeutics can cross the placenta and could potentially affect the fetal DNA.

Methodology Cord blood mononuclear cells (CBMCs) were collected from (i) pregnant breast or cervical cancer patients treated with chemotherapy regimens including carboplatin (n=7), (ii) pregnant breast cancer patients treated with chemotherapy regimens not including carboplatin (n=2), (iii) pregnant Hodgkin lymphoma patients treated with a combination of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD, n=6), (iv) non-treated pregnant breast cancer patients (n=5), and (v) healthy pregnant women (n=17). Samples were subjected to (a) cytokinesis-block micronucleus analysis to map genotoxicity via micronucleus frequencies, and (b) whole-genome sequencing of clonally expanded single cord hematopoietic stem cells (cHSCs) to identify mutational load and the presence of known exposure-related mutational signatures.

Results Micronucleus frequency was significantly increased in CBMCs from chemotherapy-treated cancer patients (2,35%) and untreated breast cancer patients (1,83%), compared to healthy pregnant women (0,69%; p<0.0001), suggesting that both the maternal cancer condition, and prenatal chemotherapy exposure are associated with genotoxic stress in CBMCs. Whole-genome sequencing revealed a significant increase in mutational load in cHSCs of all treated cases (n=12), versus healthy pregnant women (n=3; p=0.04). A platinum-specific mutational signature was found in cHSCs from patients treated with carboplatin, suggesting a direct effect of the drug on the fetal genome. cHSCs from patients treated without carboplatin showed age-related signatures, pointing to a more indirect effect upon prenatal chemotherapy exposure. Additionally, in a pilot study we observed an increased number of structural chromosomal variants in single CBMCs of n=1 ABVD-treated patient compared to n=1 healthy control.

Conclusion These findings indicate that prenatal chemotherapy exposure is correlated with increased genotoxicity in cord blood cells, pointing to direct and indirect mechanisms and depending on the type of treatment.

Disclosures NA

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