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
M. Raida et al., 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, CLIN CANC R, 7(9), 2001, pp. 2832-2839
Deficiency of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzy
me in 5-fluorouracil (5-FU) catabolism, has been linked to toxic side effec
ts of 5-FU. The most prominent 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 exo
n 14, and the enzymatic activity of the translated DPD protein is virtually
absent. We developed a reverse transcription-PCR-based assay suitable for
routine identification of the exon 14-skipping mutation and screened a cont
rol cohort of 851 Caucasian individuals as well as a cohort of 25 cancer pa
tients reported by their physicians to have suffered from WHO grades 3-4 to
xicity upon 5-FU chemotherapy. Within the control cohort, in total, eight h
eterozygotes were detected (0.94%): one heterozygote in 51 healthy donors,
(1.96%); Five heterozygotes in 572 hospital patients (0.87%); and two heter
ozygotes in 228 colorectal tumor patients (0.88%). Among the 25 patients wi
th severe 5-FU-related toxicity, 5 (20%) were heterozygous and 1 (4%) was h
omozygous for the exon 14-skipping mutation. All six patients had experienc
ed WHO grade 4 myelosuppression. Lethal outcome was seen in the homozygous
and two of the heterozygous cases. We conclude that carriers of the DPD exo
n 14-skipping mutation are at significantly increased risk to experience li
fe-threatening myelosuppression upon 5-FU treatment, even when the allelic
status is heterozygous. These data lead us to suggest routine testing for t
he exon 14-skipping mutation before 5-FU treatment.