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Nat Commun. 2019 Oct 8;10(1):4571. doi: 10.1038/s41467-019-12594-8.

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

Author information

1
Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.
2
Department of Medical Oncology, Erasmus MC Cancer institute, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
3
Center for Personalized Cancer Treatment, Rotterdam, The Netherlands.
4
Max Planck Institute for Molecular Genetics, Ihnestraße 63, 14195, Berlin, Germany.
5
Hartwig Medical Foundation Australia, Sydney, Australia.
6
Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands. ecuppen@umcutrecht.nl.
7
Center for Personalized Cancer Treatment, Rotterdam, The Netherlands. ecuppen@umcutrecht.nl.
8
Hartwig Medical Foundation, Science Park 408, 1098 XH, Amsterdam, The Netherlands. ecuppen@umcutrecht.nl.

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.

PMID:
31594944
PMCID:
PMC6783534
DOI:
10.1038/s41467-019-12594-8
[Indexed for MEDLINE]
Free PMC Article

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