The expression of CYP2A13 in human tissue was previously investigated by Su et al  who reported that this gene was transcribed predominantly in the respiratory tract. In this study, the expression of CYP2A13 was detected in non-cancerous nasopharynx and NPC tissues. The expression of CYP2A13 in biopsies of nasopharynx and the reported enzymatic activity relevant to carcinogens metabolism provided a molecular basis for determining the genetic polymorphism of CYP2A13 in NPC patients and evaluate possible associations with disease predisposition.
This is the first report on the genetic polymorphism of CYP2A13 in NPC patients. A total of 25 SNPs were identified and, among these, 11 SNPs including 424 G>A, 441 C>T, 446 T>C, 447 G>A, 454 A>T, 742 T>C, 760 T>C, 761 C>T, 867 C>G, 6958 C>T and 7196 C>T were new. In addition, we described a novel haplotype consisting of 8 SNPs within a non-coding region. Those new alleles and SNPS have been submitted to the Human Cytochrome P450 (CYP) Allele Nomenclature Committee.
In 45 NPC samples, the most frequent functional variant allele of CYP2A13 was found to be 74A-1757G-3375T-7233G. In the CYP2A13 allele nomenclature http://www.imm.ki.se/CYPalleles/cyp2a13.htm, these four SNPs were included in the allele of CYP2A13*2B. In addition to these four SNPs, CYP2A13*2B consists of eight additinal SNPs (-1479T>C; -1429A>G; -1240A>G; -411G>A; 2211T>C; 6424C>T; 6432C>T; 7571G>C). The precise phenotype/genotype correlation of this allele has not been determined. The single mutation of 3375 C>T (Arg257Cys) was firstly identified by Zhang et al (19) who then investigated the functional significance of this point mutation. Compared with the wild-type Arg-257 protein, the variant Cys-257 protein is characterized by 37% to 56% less enzymatic activity toward all substrates tested. Since CYP2A13 is highly active in the metabolic activation of several carcinogens, it was suggested that the reduction in enzymatic activity observed in variant Cys-257 could provide some protection against xenobiotic toxicity to target tissue in individuals who carry this allele. Epidemiological studies related differences in the activity of this variant to cancer susceptibility. Wang et al reported that individuals carrying the variant CYP2A13 allele (3375CT or TT) have a reduced risk of lung adenocarcinoma in relation to light tobacco smoking (OR = 0.23; 95% CI = 0.08–0.68), but no protection against lung squamous cell carcinoma was observed . However, the functional consequences of 74 G>A (Arg25Gln) in exon 1 has not been investigated yet. In an alignment of P450 sequences http://www.icgeb.org/~p450srv/, codon 25 corresponded to an Arg for CYP2A13 and to a Gln for CYP2A6 while both genes code for an Arg in codon 257. It is possible that Arg25Gln mutation has less effect on the structure and function of the CYP2A13 protein than Arg257Cys. In addition, it has not been determined whether other SNPs in noncoding regions of this haplotype may affect the transcription of this gene. Therefore, the enzymatic activity and the expression level of the phenotype associated to this allele, consequence of Arg25Gln and Arg257Cys double mutation should be investigated.
The Arg101OPA mutation represents a null allele, since the premature stop codon leads to the synthesis of a severely truncated protein 394 amino acids shorter than the wild type certainly devoid of catalytic activity. Zhang et al firstly detected this nonsense mutation in 1 of 31 Chinese individuals and not in other ethnic groups (23 White, 21 Black, 19 Hispanic, and 73 non-Chinese Asians). In the presented study, the stop mutation was detected in only 1 of 211 NPC cases and none of the 177 controls, suggesting it is a rare mutation in the Chinese population. However, Cauffiez recently reported that this deleterious mutation was the most frequent (5 %) variant allele of CYP2A13 in the French population, and that subjects heterozygous for the null allele have an elevated risk of developing small cell lung cancer (OR = 9.9; 95% CI = 1.9–52.2) . This is in contrast with the Wang's observation of a substantially reduction risk of developing lung adenocarcinoma in individuals bearing the less active allele (Arg257Cys) of CYP2A13.
We carried a case-control study in an attempt to characterize CYP2A13 genetic polymorphism and NPC susceptibility. Our results show that frequencies of most of the SNPs in controls are higher than that of NPC cases, suggesting that the mutation of this gene could provide slight protection against NPC. But, among all the investigated SNPs (in exon or intron), no significant difference was observed to draw a conclusion.
In summary, the genetic polymorphism of CYP2A13 in NPC was identified. No strong association was observed between the variant alleles and risk to develop NPC in the Cantonese population of southern China.