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1. Oncol Rep. 2012 Feb 7. doi: 10.3892/or.2012.1678. [Epub ahead of print]

Characteristic CYP2A6 genetic polymorphisms detected by TA cloning-based
sequencing in Chinese digestive system cancer patients with S-1 based

Fang WJ, Mou HB, Jin DZ, Zheng YL, Zhao P, Mao CY, Peng L, Huang MZ, Xu N.

Department of Medical Oncology, The First Affiliated Hospital, College of
Medicine, Zhejiang University, Hangzhou 310003, P.R. China.

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.

PMID: 22322240 [PubMed - as supplied by publisher]