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

Sharon Christensen, Bastiaan Roest, Nicolle Besselink, Roel Janssen, Sander Boymans, John W. M. Martens, Marie-Laure Yaspo, Peter Priestley, Ewart Kuijk, Edwin Cuppen () and Arne Van Hoeck
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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
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
Arne Van Hoeck: University Medical Center Utrecht

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12594-8

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