Dihydropyrimidine dehydrogenase (DPD) degrades over 80% of administered 5-f
luorouracil (5FU), thereby regulating the efficacy of this commonly used an
ticancer agent. DPD activity is highly variable (8-21-fold) and individuals
with reduced activity have a high risk of 5FU toxicity. DPYD encodes DPD p
rotein and 13 different mutations have been reported in DPD-deficient subje
cts. However, the contribution of these variant genotypes to polymorphic DP
D activity in vivo is not clear. The previously described DPYD mutations ar
e contained in 10 exons. These 10 exons were sequenced in a cohort of cance
r patients with reduced (n = 23) or normal (n = 14) DPD activity to determi
ne the contribution of each variant allele to low DPD activity in vivo. Eig
ht of the 13 previously defined DPYD mutations (G62A, Delta TCAT295-298, C7
03T, G1003T, G1156T, Delta C1897, G2657A, and G2983T) were not detected. A
previously defined exon 13 mutation (G1601A) was detected in three individu
als with reduced DPD activity. An exon 14 splice donor site mutation (intro
n14 G1A) was detected in a normal DPD activity individual. It was demonstra
ted that T85C, A1627G and G2194A are common polymorphisms. A novel exonic m
utation (T1679G) was detected in a patient with reduced DPD activity and 5F
U toxicity. In addition, three novel common polymorphisms were detected in
introns 10 and 13. Only three patients did not have any mutations and 30 ha
d multiple DPYD mutations in the regions examined. However, only 17% (4/23)
of the patients with a low DPD phenotype have a molecular basis for reduce
d activity. Although novel DPYD) variants have been identified in this stud
y, the 17 DPYD mutations now described do not entirely explain polymorphic
DPD activity and toxic response to 5FU. These data emphasize the complex na
ture of the molecular mechanisms controlling polymorphic DPD activity in vi
vo. Pharmacogenetics 10:217-223 (C) 2000 Lippincott Williams & Wilkins.