Rapid Detection of the DPYD IVS14+1G>A Mutation for Screening Patients to Prevent Fluorouracil-Related Toxicity
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Rapid Detection of the DPYD IVS14+1G>A Mutation for Screening Patients to Prevent Fluorouracil-Related Toxicity Tessa M. Bosch,1 Remko Bakker,2 Jan H.M. Schellens,3,4 Annemieke Cats,5 Paul H.M. Smits2 and Jos H. Beijnen1,4 1 2 3 4 5
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands Department of Molecular Biology, Slotervaart Hospital, Amsterdam, The Netherlands Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands Department of Biomedical Analysis, Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands Department of Gastroenterology and Hepatology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
Abstract
Background: Deficiency of dihydropyrimidine dehydrogenase (DPD) has been linked to severe or lethal fluorouracil (FU)-related toxicity. The most prominent mutation in the DPYD gene is the IVS14+1G>A mutation, which causes skipping of exon 14 in the messenger RNA (mRNA) and results in DPD enzyme deficiency. Several methods have been described to detect this mutation, but all are labor intensive and low throughput. Objective Our aim was to develope a high-throughput real-time PCR assay to screen patients for the IVS14+1G>A mutation. Methods: Primers and probes were developed and several reaction conditions were tested. In total, 165 individuals were screened for this mutation, with DNA sequencing as a reference method. Results: Results of the real-time PCR assay and DNA sequencing were 100% identical. In total, eight heterozygous individuals were identified, of which six were patients with severe FU-related toxicity after FU or capecitabine treatment and two were healthy volunteers. Conclusion: This new real-time PCR assay with a high throughput is particularly suitable for large-scale screening for the IVS14+1G>A mutation in patients selected for treatment with fluoropyrimidines in order to prevent severe FU-related toxicity.
Background Since its introduction in the 1950s, fluorouracil (FU) continues to be one of the most frequently used chemotherapeutic drugs for the treatment of carcinomas of the breast and colon.[1] Despite the extensive clinical experience with FU and its pro-drug capecitabine, unpredictable, severe, and even lethal toxicity still occurs during treatment with these drugs. A significant part of this FU-related toxicity has been demonstrated to be associated with the activity of dihydropyrimidine dehydrogenase (DPD), the ini-
tial and rate-limiting enzyme in the catabolism of FU.[2] Recent studies have suggested that DPD deficiency may be caused by polymorphisms in the DPYD gene.[3] To date, 39 polymorphisms have been described and studies continue to examine the relationship between DPYD genotypes and DPD phenotypes.[4-7] The most well recognized mutation associated with FU-related toxicity is the mutatio
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