Final results of a prospective multicenter study on the prevalence and genotype/phenotype correlation of the dihydropyrimidine dehydrogenase (DPD) gene exon-14 skipping mutation in patients treated with 5-fluorouracil (5-FU) chemotherapy

Abstract

3076 Background: DPD represents the initial and rate-limiting enzyme in the catabolism of 5-FU. Deficiency of DPD has been linked to toxic side effects of 5-FU. The most common mutation of the DPD gene resulting in severe DPD deficiency is a G to A mutation in the GT 5’-splice recognition site of intron 14 (exon 14 skipping mutation). The corresponding mRNA lacks exon 14 and the enzymatic activity of the translated DPD protein is virtually absent. In a clinical setting heterozygous and homozygous carriers are being observed. Methods: We developed an RT-PCR based assay suitable for routine identification of the exon 14 skipping mutation. From February 2001 to October 2004 we performed an open, uncontrolled, prospective multicenter study to evaluate the prevalence and genotype/phenotype correlation of the exon 14 skipping mutation in patients treated with 5-FU chemotherapy. 1455 patients from 70 clinical centers in Germany were included in the study. Results: We identified 15 heterozygous carriers confirming a prevalence of 1% in the Caucasian population. For the analysis of 5-FU related toxicity WHO grades were ranked with a toxicity index revealing a significant higher toxicity in heterozygous compared to wildtype patients (p<0.0001). 50% of the heterozygote patients subsequently were treated with reduced doses of 5-FU. Nonetheless the positive predictive value of the screening test was still 50% indicating a strong correlation between genotype and phenotype. To identify patients in risk of severe 5-FU related toxicity we performed 5-FU pharmacokinetics in 12 heterozygous patients and 8 wildtype patients. All heterozygous patients showed a pathological 5-FU half-life with broad variations after intravenous bolus application of 450 mg/m2 5-FU while 75% of the wildtype controls had physiological results. Conclusions: We conclude that routine testing for the exon 14 skipping mutation and additional 5-FU pharmacokinetics for heterozygous patients prior to 5-FU treatment is an important step towards individually tailored therapy in cancer patients. [Table: see text]