Prevalence of a Common Point Mutation in the Dihydropyrimidine Dehydrogenase (DPD) Gene within the 5′-Splice Donor Site of Intron 14 in Patients with Severe 5-Fluorouracil (5-FU)- related Toxicity Compared with Controls

摘要: Deficiency of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in 5-fluorouracil (5-FU) catabolism, has been linked to toxic side effects 5-FU. The most prominent mutation DPD gene resulting severe deficiency is a G A GT 5'-splice recognition site intron 14 (exon 14-skipping mutation). corresponding mRNA lacks exon 14, and enzymatic activity translated protein virtually absent. We developed reverse transcription-PCR-based assay suitable for routine identification screened control cohort 851 Caucasian individuals as well 25 cancer patients reported by their physicians have suffered from WHO grades 3-4 toxicity upon 5-FU chemotherapy. Within cohort, total, eight heterozygotes were detected (0.94%): one heterozygote 51 healthy donors, (1.96%); five 572 hospital (0.87%); two 228 colorectal tumor (0.88%). Among with 5-FU-related toxicity, 5 (20%) heterozygous 1 (4%) was homozygous mutation. All six had experienced grade 4 myelosuppression. Lethal outcome seen cases. conclude that carriers are at significantly increased risk experience life-threatening myelosuppression treatment, even when allelic status heterozygous. These data lead us suggest testing before treatment.