Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in Chinese cancer patients.
OBJECTIVE
5-fluorouracil (5-FU) is still a widely used anticancer drug. More than 85% of the 5-FU administered is catabolized by dihydropyrimidine dehydrogenase (DPD) in the liver. However, mutations in the DPD gene have been found to be associated with low DPD activity causing severe complications. The purpose of this study was to determine the mutation frequency of four exons in Chinese cancer patients and the relationship between genotype and DPD activity.


METHODS
Samples from 142 cancer patients were investigated in this study. The DPD activity was determined by reversed-phase HPLC. Exons 2, 13, 14 and 18 were amplified by polymerase chain reaction (PCR), sequenced and analysed from both sense and antisense directions. Nonparametric one-sample Kolmogorov-Smirnov test was used for distribution analysis; two independent samples t-test and one-way anova was performed for two groups and three groups analyses, respectively.


CONCLUSIONS
Plasma-DPD activities in the 142 cancer patients followed a Gaussian distribution. The mean plasma-DPD activity in women was lower than that in men (P = 0.006). Four mutations, 85T>C(DPYD*9A), 1627A>G(DPYD*5), 1896T>C and 2194G>A(DPYD*6), were found in the 142 cancer patients. The following mutations reported by others were not detected: 61C>T, 62G>A, 74A>G, 1601G>A(DPYD*4), 1679T>G(DPYD*13), 1714C>G, 1897delC(DPYD*3) and IVS 14 + 1G>A. No significant correlation was found between three mutations [85T>C(DPYD*9A), 1627A>G (DPYD*5) and 1896T>C], and DPD activity was found.


CONCLUSIONS
No clear correlation between the mutations studied and DPD activity could be established in this study. However, larger-scale prospective studies are needed to better assess the reported genotype-phenotype correlations.
He
Y-F
YF
Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Guangzhou, China.
Wei
W
W
Zhang
X
X
Li
Y-H
YH
Li
S
S
Wang
F-H
FH
Lin
X-B
XB
Li
Z-M
ZM
Zhang
D-S
DS
Huang
H-Q
HQ
Hu
B
B
Jiang
W-Q
WQ
D000368:Aged; D000704:Analysis of Variance; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D044466:Asian People; D002681:China; D002851:Chromatography, High Pressure Liquid; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D005472:Fluorouracil / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D016133:Polymerase Chain Reaction; D012737:Sex Factors
D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil