Germline mutation of dihydropyrimidine dehydrogenese gene among a Japanese population in relation to toxicity to 5-Fluorouracil.
5-Fluorouracil (5FU) is most commonly used in chemotherapy for human malignancy. Over 80% of administered 5FU is metabolically degraded by dihydropyrimidine dehydrogenase (DPD), a primary and rate-limiting enzyme in the 5FU metabolic pathway. A DPD-deficient phenotype among cancer patients, which has posed a serious problem in 5FU-based chemotherapy, was reported to be in part ascribed to germline mutations in dihydropyrimidine dehydrogenase (DPYD) gene. Therefore, we for the first time examined the frequencies and types of germline mutations in the DPYD gene among a total of 107 Japanese cancer patients and healthy volunteers. Of 214 alleles examined among them, 181 alleles were of the same type, which was assigned as wild type; 21 alleles revealed a nucleotide substitution resulting in silent mutation; and the remaining 12 alleles showed five types of nucleotide deletion or substitutions resulting in one frameshift and four missense mutations. Three of them, A74G, 812delT and L572V, were novel mutations. None of the study subjects showed homozygous frameshift or missense mutated alleles. We also studied the association between toxic response to 5FU and heterozygous frame shift or missense mutation of the DPYD gene among eight cancer patients who had received 5FU-based chemotherapy. These patients did not show any adverse effects higher than grade 3, suggesting that heterozygotes are not associated with increased toxicity to 5FU. Our results indicate that a very small percentage, about 0.2%, of the Japanese population seems to carry homozygous mutations in DPYD gene, mutations which possibly indicate genetically increased toxicity of 5FU-based chemotherapy.
Saitama Cancer Center Hospital, Ina, Kitaadachi-gun, Saitama 362-0806, Japan. k-yamaguchi@cancer-c.pref.saitama.jp
K
K
Yamaguchi
Y
Y
Arai
Y
Y
Kanda
K
K
Akagi
D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D044466:Asian People; D001483:Base Sequence; D001711:Biotransformation; D004247:DNA / Q000097:blood; D042943:Dihydrouracil Dehydrogenase (NADP); D005260:Female; D005472:Fluorouracil / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016368:Frameshift Mutation; D018095:Germ-Line Mutation; D006801:Humans; D007564:Japan; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009369:Neoplasms / Q000188:drug therapy*; D010088:Oxidoreductases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D012016:Reference Values; D017384:Sequence Deletion
D000964:Antimetabolites, Antineoplastic; D004247:DNA; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil