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5-Fluorouracil treatment induces characteristic T>G mutations in human cancer

Author

Listed:
  • Sharon Christensen

    (University Medical Center Utrecht)

  • Bastiaan Roest

    (University Medical Center Utrecht)

  • Nicolle Besselink

    (University Medical Center Utrecht)

  • Roel Janssen

    (University Medical Center Utrecht)

  • Sander Boymans

    (University Medical Center Utrecht)

  • John W. M. Martens

    (Erasmus University Medical Center
    Center for Personalized Cancer Treatment)

  • Marie-Laure Yaspo

    (Max Planck Institute for Molecular Genetics)

  • Peter Priestley

    (Hartwig Medical Foundation Australia)

  • Ewart Kuijk

    (University Medical Center Utrecht)

  • Edwin Cuppen

    (University Medical Center Utrecht
    Center for Personalized Cancer Treatment
    Hartwig Medical Foundation)

  • Arne Van Hoeck

    (University Medical Center Utrecht)

Abstract

5-Fluorouracil (5-FU) is a chemotherapeutic drug commonly used for the treatment of solid cancers. It is proposed that 5-FU interferes with nucleotide synthesis and incorporates into DNA, which may have a mutational impact on both surviving tumor and healthy cells. Here, we treat intestinal organoids with 5-FU and find a highly characteristic mutational pattern that is dominated by T>G substitutions in a CTT context. Tumor whole genome sequencing data confirms that this signature is also identified in vivo in colorectal and breast cancer patients who have received 5-FU treatment. Taken together, our results demonstrate that 5-FU is mutagenic and may drive tumor evolution and increase the risk of secondary malignancies. Furthermore, the identified signature shows a strong resemblance to COSMIC signature 17, the hallmark signature of treatment-naive esophageal and gastric tumors, which indicates that distinct endogenous and exogenous triggers can converge onto highly similar mutational signatures.

Suggested Citation

  • Sharon Christensen & Bastiaan Roest & Nicolle Besselink & Roel Janssen & Sander Boymans & John W. M. Martens & Marie-Laure Yaspo & Peter Priestley & Ewart Kuijk & Edwin Cuppen & Arne Van Hoeck, 2019. "5-Fluorouracil treatment induces characteristic T>G mutations in human cancer," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12594-8
    DOI: 10.1038/s41467-019-12594-8
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    Cited by:

    1. Eline J. M. Bertrums & Jurrian K. Kanter & Lucca L. M. Derks & Mark Verheul & Laurianne Trabut & Markus J. Roosmalen & Henrik Hasle & Evangelia Antoniou & Dirk Reinhardt & Michael N. Dworzak & Nora Mü, 2024. "Selective pressures of platinum compounds shape the evolution of therapy-related myeloid neoplasms," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Bernard C. H. Lee & Philip S. Robinson & Tim H. H. Coorens & Helen H. N. Yan & Sigurgeir Olafsson & Henry Lee-Six & Mathijs A. Sanders & Hoi Cheong Siu & James Hewinson & Sarah S. K. Yue & Wai Yin Tsu, 2022. "Mutational landscape of normal epithelial cells in Lynch Syndrome patients," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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