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.

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Persistent URL dx.doi.org/10.1038/s41467-019-12594-8, hdl.handle.net/1765/120215
Journal Nature Communications
Christensen, S. (Sharon), Van der Roest, B. (Bastiaan), Besselink, N, Janssen, R. (Roel), Boymans, S. (Sander), Martens, J.W.M, … Van Hoeck, A. (Arne). (2019). 5-Fluorouracil treatment induces characteristic T>G mutations in human cancer. Nature Communications, 10(1). doi:10.1038/s41467-019-12594-8