• Cancer Chemother. Pharmacol. · Oct 2016

    Patients homozygous for DPYD c.1129-5923C>G/haplotype B3 have partial DPD deficiency and require a dose reduction when treated with fluoropyrimidines.

    • Didier Meulendijks, Linda M Henricks, André B P van Kuilenburg, Bart A W Jacobs, Abidin Aliev, Lisette Rozeman, Judith Meijer, Jos H Beijnen, Hiltje de Graaf, Annemieke Cats, and Jan H M Schellens.
    • Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. didier.meulendijks@gmail.com.
    • Cancer Chemother. Pharmacol. 2016 Oct 1; 78 (4): 875-80.

    PurposeDihydropyrimidine dehydrogenase (DPD) is a critical determinant of 5-fluorouracil pharmacology, and reduced activity of DPD as a result of deleterious polymorphisms in the gene encoding DPD (DPYD) can result in severe treatment-related toxicity. Dosing recommendations to individualize treatment have been provided for three DPYD variants (DPYD*2A, c.2846A>T, and c.1679T>G). A fourth variant, c.1129-5923C>G/HapB3, has been shown to increase the risk of fluoropyrimidine-associated toxicity, but little is known about the functional effects of this variant.MethodsBy performing a large retrospective screen for DPYD variants, we identified three patients who were homozygous for c.1129-5923C>G/HapB3. We describe their clinical course of treatment and analyzed DPD activity and DPYD gene expression, to provide insight into the phenotypic effects of c.1129-5923C>G/HapB3.ResultsDPD activity could be measured in two patients and was 4.1 and 5.4 nmol/mg/h (DPD activity 41 and 55 % compared to controls, respectively). The fluoropyrimidine dose had to be reduced during treatment in both patients. In line with partial DPD deficiency in both patients, sequence analysis of DPD cDNA demonstrated a normal-sized (wild type) cDNA fragment of 486 bp, as well as a larger-sized (mutant) 530-bp fragment containing an aberrant 44-bp insertion in intron 10. Patient three tolerated treatment well, but DPD activity measurement was not possible as the patient had deceased at the time of performing the study.ConclusionsThe presented functional and clinical data indicate that the c.1129-5923C>G variant is both functionally and clinically relevant, and support an upfront dose reduction of the fluoropyrimidine starting dose in patients carrying c.1129-5923C>G homozygously.

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