Preemptive screening of DPYD as part of clinical practice: high prevalence of a novel exon 4 deletion in the Finnish population

Capecitabine is a fluoropyrimidine that is widely used as a cancer drug for the treatment of patients with a variety of cancers. Unfortunately, early onset, severe or life-threatening toxicity is observed in 19-32% of patients treated with capecitabine and 5FU. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the degradation of 5FU and a DPD deficiency has been shown to be a major determinant of severe fluoropyrimidine-associated toxicity. DPD is encoded by the DPYD gene and some of the identified variants have been described to cause DPD deficiency. Preemptive screening for DPYD gene alterations enables the identification of DPD-deficient patients before administering fluoropyrimidines. In this article, we describe the application of upfront DPD screening in Finnish patients, as a part of daily clinical practice, which was based on a comprehensive DPYD gene analysis, measurements of enzyme activity and plasma uracil concentrations. Almost 8% of the patients (13 of 167 patients) presented with pathogenic DPYD variants causing DPD deficiency. The DPD deficiency in these patients was further confirmed via analysis of the DPD activity and plasma uracil levels. Interestingly, we identified a novel intragenic deletion in DPYD which includes exon 4 in four patients (31% of patients carrying a pathogenic variant). The high prevalence of the exon 4 deletion among Finnish patients highlights the importance of full-scale DPYD gene analysis. Based on the literature and our own experience, genotype preemptive screening should always be used to detect DPD-deficient patients before fluoropyrimidine therapy.

Automated summary

This study describes the application of upfront DPD screening in Finnish patients, revealing that 8% of patients carried pathogenic DPYD variants causing DPD deficiency, including a novel intragenic deletion. The high prevalence of exon 4 deletion among Finnish patients emphasizes the importance of full-scale DPYD gene analysis and the use of genotype preemptive screening to detect DPD-deficient patients before fluoropyrimidine therapy.