In their latest paper in Nature Communications, Oncode Investigator Edwin Cuppen and Arne van Hoeck (UMC Utrecht), together with colleagues, assess the mutational impact of fluoropyrimidines. Systematic analysis of genome-wide cancer data has revealed mutational signatures that represent the mutational consequences of a mutational process. Some signatures have been linked to perturbed endogenous processes like deficient DNA repair, while others have been attributed to an exogenous mutagen such as UV-light or smoking. Fluoropyrimidines, especially 5-Fluorouracil (5-FU) and capecitabine, are commonly used for the treatment of solid cancer including colorectal and breast cancer. The researchers propose that 5-FU possesses anticancer properties via the interference with nucleotide synthesis and incorporate into DNA. As both mechanisms may induce mutations in tumor surviving cells, they have assessed the mutational impact of fluoropyrimidines.

We spoke with Arne van Hoeck about the research.

What is the most important finding of your research?

“Using small intestinal organoids, we demonstrate that fluoropyrimidines are mutagenic and leave a characteristic mutational signature that is dominated by T>G mutations. We identified the same mutational signature in vivo in colorectal and breast cancer patients that have undergone treatment with fluoropyrimidines. As such, our work shows that fluoropyrimidines activate a mutational process that almost exclusively induces T>G point mutations. Intriguingly, the observed 5-FU signature is identical to an already existing signature that currently lacks any etiology, but that is mostly seen in untreated gastric and esophagus cancers. This indicates that distinct endogenous and exogenous triggers can converge onto highly similar mutational signatures and thus may activate the same mutational process.”

Why is this type of research so important?

“We show that fluoropyrimidine treatment increases the mutation rate in human cancer and thus drive tumor evolution and progression by inducing novel mutations related to oncogenic or resistance mechanisms. However, it can be postulated that not only cancer cells, but any other cell in the body exposed to fluoropyrimidines accumulate mutations, which could lead to the onset of secondary malignancies. As such, our finding may be relevant for treatment decision makers who must be aware of the increased risk factors of 5-FU administration to cancer patients at a relatively young age.”