Characteristic CYP2A6 genetic polymorphisms detected by TA cloning-based             sequencing in Chinese digestive system cancer patients with S-1 based chemotherapy.
S-1 is an oral antitumor agent that contains tegafur, which is converted             to fluorouracil (5-FU) in the human body. Cytochrome P450 2A6 (CYP2A6) is the             principal enzyme responsible for bioconversion of tegafur to 5-FU. A number of             CYP2A6 polymorphisms have been associated with variations in enzyme activity in             several ethnic populations. The CYP2A6*4C allele leads to deletion of the entire             CYP2A6 gene, and is the main finding in patients with reduced CYP2A6 enzymatic             activity. Thus, the aim of our study was to evaluate the allele frequencies of             CYP2A6 polymorphisms in a population with cancer of the digestive system. We developed             a simple screening method, which combined TA cloning and direct-sequencing, to             detect CYP2A6 genetic polymorphisms in Chinese patients with cancers of the digestive             system. A total of 77 patients with various types of digestive system cancers             were screened for CYP2A6 genetic polymorphisms. The allele frequencies of CYP2A6*1A,             CYP2A6*1B and CYP2A6*4C in the 77 patients screened were 62, 42 and 13%, respectively.             Frequencies of the homozygous genotypes for CYP2A6*1A and CYP2A6*4C were 27 and             12%, respectively. As expected, patients that were determined to be homozygous             for CYP2A6*4C exhibited the characteristic chemotherapy efficacy and toxicity             profiles. The TA cloning-based direct sequencing method facilitated allele frequency             and genotyping determination for CYP2A6*1A, 1B and 4C of cancer patients. The             findings indicated that the population carries a high frequency of the CYP2A6*4C             homozygous genotype. Thus, the reduced efficacy of standard chemotherapy dosage             in Chinese cancer patients may be explained by the lack of CYP2A6-mediated S-1             bioconversion to 5-FU.
Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, PR China.
Wei-Jia
WJ
Fang
Hai-Bo
HB
Mou
Da-Zhi
DZ
Jin
Yu-Long
YL
Zheng
Peng
P
Zhao
Chen-Yu
CY
Mao
Ling
L
Peng
Ming-Zhu
MZ
Huang
Nong
N
Xu
D000293:Adolescent; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001483:Base Sequence; D065637:Cytochrome P-450 CYP2A6; D004067:Digestive System Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D004338:Drug Combinations; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010094:Oxonic Acid / Q000009:adverse effects / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D005641:Tegafur / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6