CYP2A6

Gene Summary

Gene:CYP2A6; cytochrome P450, family 2, subfamily A, polypeptide 6
Aliases: CPA6, CYP2A, CYP2A3, P450PB, CYPIIA6, P450C2A
Location:19q13.2
Summary:This gene, CYP2A6, encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by phenobarbital. The enzyme is known to hydroxylate coumarin, and also metabolizes nicotine, aflatoxin B1, nitrosamines, and some pharmaceuticals. Individuals with certain allelic variants are said to have a poor metabolizer phenotype, meaning they do not efficiently metabolize coumarin or nicotine. This gene is part of a large cluster of cytochrome P450 genes from the CYP2A, CYP2B and CYP2F subfamilies on chromosome 19q. The gene was formerly referred to as CYP2A3; however, it has been renamed CYP2A6. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:cytochrome P450 2A6
HPRD
Source:NCBIAccessed: 16 March, 2015

Ontology:

What does this gene/protein do?
Show (14)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 16 March 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Singapore
  • Cytochrome P-450 Enzyme System
  • Chromosome 19
  • Colorectal Cancer
  • Antimetabolites, Antineoplastic
  • Glutathione Transferase
  • Smoking
  • Carcinogens
  • Single Nucleotide Polymorphism
  • Uric Acid
  • Nicotine
  • Oxonic Acid
  • Drug Combinations
  • Cytochrome P-450 CYP2A6
  • Transfection
  • Case-Control Studies
  • Spain
  • Genetic Predisposition
  • Alleles
  • Polymorphism
  • Asian Continental Ancestry Group
  • Steroid Hydroxylases
  • Japan
  • CYP2A6
  • Aryl Hydrocarbon Hydroxylases
  • Messenger RNA
  • Genotype
  • Risk Factors
  • Esophageal Cancer
  • Restriction Fragment Length Polymorphism
  • Gene Deletion
  • Smoking and Smoking Cessation
  • Odds Ratio
  • Mixed Function Oxygenases
  • Cytochrome P-450 CYP1A1
  • Stomach Cancer
  • Young Adult
  • Genetic Variation
  • Sri Lanka
  • Retroviridae
  • Lung Cancer
Tag cloud generated 16 March, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CYP2A6 (cancer-related)

Ren F, Wang DB, Li T, et al.
Identification of differentially methylated genes in the malignant transformation of ovarian endometriosis.
J Ovarian Res. 2014; 7:73 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Key roles for epigenetic mechanisms in tumorigenesis are well accepted, while the relationship between gene methylation and malignant transformation of ovarian endometriosis (EMS) was seldom reported. In this study, we aimed to screen for aberrantly methylated genes associated with the malignant transformation of ovarian EMS and to preliminarily verify the reliability of screened results by detecting the methylation status and protein expression of the candidate gene in a larger scale of formaldehyde-fixed and paraffin-embedded (FFPE) samples.
METHODS: Methylated CpG island amplification coupled with representational difference analysis (MCA-RDA) was performed on 3 couples of endometriosis-associated ovarian carcinoma (EAOC) fresh samples to identify differentially methylated candidate genes related to malignant transformation of ovarian EMS; Methylation-specific PCR (MSP) and immunohistochemistry were performed in 30 EAOC samples to detected the methylation status and protein expression of RASSF2 gene to verify the reliability of MCA-RDA results.
RESULTS: Nine differentially methylated genes were obtained by MCA-RDA as candidate genes for malignant transformation of EMS; Methylation frequency of RASSF2 in the neoplastic tissues of EAOC group was higher than that in the ectopic endometria (p < 0.05). While protein expression of RASSF2 in the neoplastic tissues was lower than that in the ectopic endometria of the EAOC group (p < 0.05) Absence of protein expression of RASSF2 was significantly correlated with the promoter methylation of the gene (p < 0.05).
CONCLUSIONS: RASSF2, RUNX3, GSTZ1, CYP2A, GBGT1, NDUFS1, SPOCK2, ADAM22, and TRIM36 were candidate genes for malignant transformation of ovarian EMS and epigenetic inactivation of RASSF2 by promoter hypermethylation is an early event in malignant transformation of ovarian EMS. The screen results were reliable and worthy of further study.

Hocevar BA, Kamendulis LM, Pu X, et al.
Contribution of environment and genetics to pancreatic cancer susceptibility.
PLoS One. 2014; 9(3):e90052 [PubMed] Free Access to Full Article Related Publications
Several risk factors have been identified as potential contributors to pancreatic cancer development, including environmental and lifestyle factors, such as smoking, drinking and diet, and medical conditions such as diabetes and pancreatitis, all of which generate oxidative stress and DNA damage. Oxidative stress status can be modified by environmental factors and also by an individual's unique genetic makeup. Here we examined the contribution of environment and genetics to an individual's level of oxidative stress, DNA damage and susceptibility to pancreatic cancer in a pilot study using three groups of subjects: a newly diagnosed pancreatic cancer group, a healthy genetically-unrelated control group living with the case subject, and a healthy genetically-related control group which does not reside with the subject. Oxidative stress and DNA damage was evaluated by measuring total antioxidant capacity, direct and oxidative DNA damage by Comet assay, and malondialdehyde levels. Direct DNA damage was significantly elevated in pancreatic cancer patients (age and sex adjusted mean ± standard error: 1.00 ± 0.05) versus both healthy unrelated and related controls (0.70 ± 0.06, p<0.001 and 0.82 ± 0.07, p = 0.046, respectively). Analysis of 22 selected SNPs in oxidative stress and DNA damage genes revealed that CYP2A6 L160H was associated with pancreatic cancer. In addition, DNA damage was found to be associated with TNFA -308G>A and ERCC4 R415Q polymorphisms. These results suggest that measurement of DNA damage, as well as select SNPs, may provide an important screening tool to identify individuals at risk for development of pancreatic cancer.

Lin CY, Pan TS, Ting CC, et al.
Cytochrome p450 metabolism of betel quid-derived compounds: implications for the development of prevention strategies for oral and pharyngeal cancers.
ScientificWorldJournal. 2013; 2013:618032 [PubMed] Free Access to Full Article Related Publications
Betel quid (BQ) products, with or without tobacco, have been classified by the International Agency for Research on Cancer (IARC) as group I human carcinogens that are associated with an elevated risk of oral potentially malignant disorders (OPMDs) and cancers of the oral cavity and pharynx. There are estimated 600 million BQ users worldwide. In Taiwan alone there are 2 million habitual users (approximately 10% of the population). Oral and pharyngeal cancers result from interactions between genes and environmental factors (BQ exposure). Cytochrome p450 (CYP) families are implicated in the metabolic activation of BQ- and areca nut-specific nitrosamines. In this review, we summarize the current knowledge base regarding CYP genetic variants and related oral disorders. In clinical applications, we focus on cancers of the oral cavity and pharynx and OPMDs associated with CYP gene polymorphisms, including CYP1A1, CYP2A6, CYP2E1, and CYP26B1. Our discussion of CYP polymorphisms provides insight into the importance of screening tests in OPMDs patients for the prevention of oral and pharyngeal cancers. Future studies will establish a strong foundation for the development of chemoprevention strategies, polymorphism-based clinical diagnostic tools (e.g., specific single-nucleotide polymorphism (SNP) "barcodes"), and effective treatments for BQ-related oral disorders.

Kim SY, S Hong Y, K Shim E, et al.
S-1 plus irinotecan and oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: a prospective phase II study and pharmacogenetic analysis.
Br J Cancer. 2013; 109(6):1420-7 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: S-1 is an oral fluoropyrimidine that mimics infusional 5-fluorouracil. The aim of this phase II trial was to explore the clinical efficacy of the triplet regimen TIROX, which consists of S-1, irinotecan and oxaliplatin.
METHODS: Forty-two chemo-naive patients with metastatic colorectal cancer (mCRC) were planned to be enrolled and be treated with irinotecan 150 mg m(-2) followed by oxaliplatin 85 mg m(-2) on day 1 and S-1 80 mg m(-2) per day from day 1 to 14 every 3 weeks. Polymorphisms in the UGT1A1, UGT1A6, UGT1A7 and CYP2A6 genes were analysed.
RESULTS: Between July 2007 and February 2008, 43 patients were enrolled. An objective response was noted in 29 patients (67.4%, 95% confidence interval: 53.4-81.4), of which 2 achieved durable complete responses. The median progression-free survival was 10.0 months and the median overall survival was 19.2 months. Significant grade 3 or 4 adverse events were neutropenia (45.2%), febrile neutropenia (9.5%), diarrhoea (7.1%) and vomiting (9.5%). Increased gastrointestinal toxicities were associated with the presence of UGT1A6*2 or UGT1A7*3 and an improved tumour response was noted in those without variant alleles of CYP2A6 or UGT1A1*60.
CONCLUSION: The combination of S-1, irinotecan and oxaliplatin showed favourable efficacy and tolerability in untreated patients with mCRC.

Liu YL, Xu Y, Li F, et al.
CYP2A6 deletion polymorphism is associated with decreased susceptibility of lung cancer in Asian smokers: a meta-analysis.
Tumour Biol. 2013; 34(5):2651-7 [PubMed] Related Publications
Cytochrome P450 2A6 (CYP2A6) is an enzyme involved in the metabolism of some tobacco carcinogens, which is an important risk factor of lung cancer. Among CYP2A6 allelic variants, CYP2A6*4 presents a whole gene deletion that accounts for the majority of poor metabolizer. In this study, a meta-analysis was performed to assess the association between CYP2A6*4 and risk of lung cancer. Literature searches were conducted to identify peer-reviewed manuscripts published up to December 20, 2012. Pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were calculated in a fixed-effects model and a random-effects model when appropriate. Eight eligible studies with 3,203 lung cancer cases and 2,839 controls were included in this study. Overall, no significant association was observed in CYP2A6*4 with the risk of lung cancer under any genetic model for all samples after correction. However, subgroup analysis showed that significant associations were observed in Asian with pooled OR (95 %CI) of 0.761 (0.672-0.861) for allele comparison, 0.769 (0.668-0.886) for dominant model, and 0.522 (0.359-0.760) for recessive model. Furthermore, after stratifying Asian samples according to smoking status, significant associations were only observed in smokers with pooled OR (95 %CI) of 0.713 (0.607-0.838) for allele comparison, 0.720 (0.596-0.869) for dominant model, and 0.444 (0.275-0.715) for recessive model. This meta-analysis suggests that the CYP2A6*4 polymorphism was associated with susceptibility of lung cancer for smokers in Asian. The whole gene deletion of CYP2A6 might decrease the risk of tobacco-related lung cancer in Asian.

Wang L, Zang W, Liu J, et al.
Association of CYP2A6*4 with susceptibility of lung cancer: a meta-analysis.
PLoS One. 2013; 8(4):e59556 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: To assess the association between the variant of Cytochrome P450 2A6 whole gene deletion (CYP2A6*4) polymorphism and risk of lung cancer.
METHODS: Two investigators independently searched the PubMed, Elsevier, EMBASE, Web of Science, Wiley Online Library and Chinese National Knowledge Infrastructure (CNKI). Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) for CYP2A6*4 and lung cancer were calculated in a fixed-effects model (the Mantel-Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate.
RESULTS: This meta-analysis included seven eligible studies, which included 2524 lung cancer cases and 2258 controls (cancer-free). Overall, CYP2A6*4 was associated with the risk of lung cancer (allele*4 vs. allele non-*4, pooled OR  = 0.826, 95% CI  = 0.725-0.941, P-value  = 0.004). When stratifying for population, significant association was observed in Asian (additive model, pooled OR  = 0.794, 95% CI  = 0.694-0.909, P-value  = 0.001; dominant model, pooled OR  = 0.827, 95% CI  = 0.709-0.965, P-value  = 0.016; recessive model (pooled OR  = 0.444, 95% CI  = 0.293-0.675, P-value <0.0001). In the overall analysis, a comparably significant decrease in the frequency of *4/*4 genotype was detected between cases and controls in Asian while no *4/*4 genotype was detected in Caucasian in collected data.
CONCLUSION: This meta-analysis suggests that the CYP2A6*4 polymorphism is associated with susceptibility of lung cancer in Asian. The whole gene deletion of CYP2A6 may decrease the risk of lung cancer in Asian samples.

Styn MA, Nukui T, Romkes M, et al.
CYP2A6 genotype and smoking behavior in current smokers screened for lung cancer.
Subst Use Misuse. 2013; 48(7):490-4 [PubMed] Free Access to Full Article Related Publications
Functional CYP2A6 genetic variation partially determines nicotine metabolism. In 2005, we examined functional CYP2A6 variants associated with reduced metabolism (CYP2A6*2, CYP2A6*9, CYP2A6*4), smoking history, and change in smoking in 878 adult smokers undergoing lung cancer screening in an urban setting. At one year, 216 quit smoking for more than 30 days while 662 continued smoking. Compared to subjects who smoked 30 cigarettes per day at baseline, the odds of a reduced metabolism genotype was 52% higher in subjects smoking 20-29 cigarettes per day and 86% higher in subjects smoking less than 20 cigarettes per day (p-trend = 0.016). Reduced metabolism genotypes appeared unrelated to quitting. Though related to smoking dose, CYP2A6 may not influence cessation.

Huang FM, Chen HC, Khan MA, et al.
CYP2A6, CYP1A1, and CYP2D6 polymorphisms in lung cancer patients from central south China.
Med Oncol. 2013; 30(2):521 [PubMed] Related Publications
Lung cancer is a common cause of cancer-related death. The link between risk of lung cancer susceptibility and genetic polymorphisms in metabolic enzymes is well documented. In this study, the relationships between lung cancer susceptibility and polymorphisms in the phase I metabolic enzyme genes CYP1A1, CYP2D6, and CYP2A6 were investigated. Genomic DNA was isolated from the peripheral blood of 201 healthy controls and 168 lung carcinoma patients from the Han ethnic group of Hunan Province in Central South China. Polymorphisms of the investigated genes were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and two-step allelic-specific PCR assays. No significant differences were found between the frequencies in cases and controls for the genotypes wild-type (WW), heterozygous mutant, or homozygous mutant; for CYP1A1 or CYP2D6; or for the genotypes WW, heterozygous deletion, or null genotype for CYP2A6. The three-locus model (CYP2A6/CYP1A1/CYP2D6) had a maximum test sample accuracy that was significant (P < 0.001) with a cross-validation consistency of 10. These results indicated that the three-order interaction of CYP2A6, CYP1A1, and CYP2D6 polymorphisms might increase genetic susceptibility to lung cancer. We report the involvement of a three-order interaction between CYP1A1, CYP2A6, and CYP2D6 polymorphisms in lung cancer risk in people in Central South China, although no relationship between lung cancer risk and individual gene polymorphisms was found.

Liu T, Xie CB, Ma WJ, Chen WQ
Association between CYP2A6 genetic polymorphisms and lung cancer: a meta-analysis of case-control studies.
Environ Mol Mutagen. 2013; 54(2):133-40 [PubMed] Related Publications
Cytochrome P450 2A6 (CYP2A6) is an enzyme responsible for the metabolism of nicotine and some tobacco-specific carcinogens (such as N-nitrosamines). CYP2A6 genetic variations are associated with the activity of the CYP2A6 enzyme, which affects smoking behavior and the rate at which some tobacco-specific carcinogens are metabolized, which in turn determines the incidence of lung cancer. Several studies have investigated the relationship between CYP2A6 genotypes and lung cancer; however, the results are controversial. In this meta-analysis, we searched for all studies on the association between CYP2A6 genotypes and lung cancer indexed in the MEDLINE, PubMed, Embase, China Biological Medicine, and Wanfang databases from January 1, 1966 to August 1, 2011. The pooled odds ratios (ORs) for one CYP2A6 mutant allele and two CYP2A6 mutant alleles, in comparison with the wild-type CYP2A6 gene, were 0.82 [95% confidence interval (CI) = 0.73-0.92] and 0.57 (95% CI = 0.48-0.68), respectively. Furthermore, in two studies of participants who were all smokers, the associations of one CYP2A6 mutant allele and two CYP2A6 mutant alleles with reduced risk of lung cancer were strengthened, and the pooled ORs were 0.71 (95% CI = 0.58-0.87) and 0.47 (95% CI = 0.35-0.62), respectively. However, we did not find statistically significant relationships between CYP2A6 genotypes and lung cancer in studies that included both never smokers and smokers (pooled OR(one CYP2A6 mutant allele) = 0.88, 95% CI = 0.76-1.01; pooled OR(two CYP2A6 mutant alleles) = 0.61, 95% CI = 0.35-1.06). The results of this meta-analysis suggest that the reduced-activity CYP2A6 genotype may decrease the risk of lung cancer in smokers only.

Islam MS, Ahmed MU, Sayeed MS, et al.
Lung cancer risk in relation to nicotinic acetylcholine receptor, CYP2A6 and CYP1A1 genotypes in the Bangladeshi population.
Clin Chim Acta. 2013; 416:11-9 [PubMed] Related Publications
BACKGROUND: CYP1A1, CYP2A6 and CHRNA5 are biologically plausible genes as risk factors for lung cancer but no studies have been reported in the Bangladeshi population.
METHODS: We conducted this study to determine the prevalence and role of CYP1A1, CYP2A6 and CHRNA5 polymorphisms together with tobacco smoking in the development of lung cancer in Bangladesh. A case-control study was carried out on 106 lung cancer patients and 116 controls to investigate three allelic variants of the CYP1A1 gene-rs4646903, rs1048943 and rs1799814; 2 variants of CYP2A6 (CYP2A6*1B1, CYP2A6*4) and 1 variant of CHRNA5 (rs16969968) using Polymerase Chain Reaction Restriction Fragment Length Polymorphism.
RESULTS: Lung cancer risk was estimated as odds ratio (OR) and 95% confidence interval (CI) using unconditional logistic regression models adjusting for age, sex and smoking. A significantly elevated lung cancer risk was associated with heterozygous, mutant and combined heterozygous plus mutant variants of CYP1A1 rs4646903. A significant association was also found for heterozygous and heterozygous plus mutant variants of rs1048943 which was in linkage disequilibrium with rs4646903. The risk of lung cancer was decreased significantly in individuals carrying at least one CYP2A6 deletion (CYP2A6*4) allele. No association with lung cancer risk was found for CHRNA5 rs16969968. When stratified by smoking, the effects of CYP1A1 and CYP2A6 polymorphisms on lung cancer susceptibility were found to be significant only in heavy smokers who had smoked 40 pack years or more (54% of all cases) but no associations were seen for lighter smokers. No association was also found with any polymorphism in the non-smokers in this study.
CONCLUSIONS: Our results indicate that the CYP1A1*2B allele (rs4646903 and rs1048943) is associated with an increased lung cancer risk and CYP2A6*4 is associated with a decreased lung cancer risk in the study population.

Raunio H, Rahnasto-Rilla M
CYP2A6: genetics, structure, regulation, and function.
Drug Metabol Drug Interact. 2012; 27(2):73-88 [PubMed] Related Publications
The human CYP2A gene subfamily consists of three members, CYP2A6, CYP2A7, and CYP2A13. The CYP2A6 gene is highly polymorphic with approximately 40 annotated allelic variants. Individuals homozygous for some of these alleles have a total lack of CYP2A6 activity. The CYP2A6 protein is most abundant in liver and is expressed, although at much lower levels, in some other tissues, especially nasal mucosa. CYP2A6 differs from other human liver CYP forms in that it participates in the metabolism of very few currently used drugs. The two most relevant substrates for CYP2A6 are coumarin and nicotine. Coumarin is the marker substance for determining CYP2A6 activity both in vitro and in vivo. Approximately 80% of a nicotine dose is eliminated by CYP2A6, and there is a clear link between CYP2A6 genotypes, smoking behavior, and lung cancer risk.

Fang WJ, Mou HB, Jin DZ, et al.
Characteristic CYP2A6 genetic polymorphisms detected by TA cloning-based sequencing in Chinese digestive system cancer patients with S-1 based chemotherapy.
Oncol Rep. 2012; 27(5):1606-10 [PubMed] Related Publications
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.

Desta Z, Kreutz Y, Nguyen AT, et al.
Plasma letrozole concentrations in postmenopausal women with breast cancer are associated with CYP2A6 genetic variants, body mass index, and age.
Clin Pharmacol Ther. 2011; 90(5):693-700 [PubMed] Free Access to Full Article Related Publications
The associations between plasma letrozole concentrations and CYP2A6 and CYP3A5 genetic variants were tested in the Exemestane and Letrozole Pharmacogenomics (ELPH) trial. ELPH is a multicenter, open-label prospective clinical trial in women randomly assigned (n≈250 in each arm) to receive 2 years of treatment with either oral letrozole (2.5 mg/day) or oral exemestane (25 mg/day). CYP2A6 and CYP3A showed effects on letrozole metabolism in vitro. DNA samples were genotyped for variants in the CYP2A6 and CYP3A5 genes. Plasma letrozole concentrations showed high interpatient variability (>10-fold) and were associated significantly with CYP2A6 genotypes (P<0.0001), body mass index (BMI) (P<0.0001), and age (P=0.0035). However, CYP3A5 genotypes showed no association with plasma letrozole concentrations. These data suggest that CYP2A6 is the principal clearance mechanism for letrozole in vivo. CYP2A6 metabolic status, along with BMI and age, may serve as a biomarker of the efficacy of letrozole treatment or a predictor of adverse effects.

Tamaki Y, Arai T, Sugimura H, et al.
Association between cancer risk and drug-metabolizing enzyme gene (CYP2A6, CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1) polymorphisms in cases of lung cancer in Japan.
Drug Metab Pharmacokinet. 2011; 26(5):516-22 [PubMed] Related Publications
Genetic polymorphisms of enzymes involved in the metabolism of carcinogens are suggested to modify an individual's susceptibility to lung cancer. The purpose of this study was to investigate the relationship between lung cancer cases in Japan and variant alleles of cytochrome P450 (CYP) 2A6 (CYP2A6*4), CYP2A13 (CYP2A13*1-*10), CYP4B1 (CYP4B1*1-*7), sulfotransferase 1A1 (SULT1A1*2), glutathione S-transferase M1 (GSTM1 null), and glutathione S-transferase T1 (GSTT1 null). We investigated the distribution of these polymorphisms in 192 lung cancer patients and in 203 age- and sex-matched cancer-free controls. The polymorphisms were analyzed using various techniques including allele-specific PCR, hybridization probe assay, multiplex PCR, denaturing high-performance liquid chromatography (DHPLC), and direct sequencing. We also investigated allele and genotype frequencies and their association with lung cancer risk, demographic factors, and smoking status. The prevalence of the CYP2A6*4/*4 genotype in lung cancer cases was 3.6%, compared with 9.4% in the controls (adjusted OR = 0.36, 95% CI = 0.15-0.88, P = 0.025). In contrast, there was no association between the known CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1 polymorphisms and lung cancer. These data indicate that CYP2A6 deletions may be associated with lung cancer in the Japanese population studied.

Wassenaar CA, Dong Q, Wei Q, et al.
Relationship between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 variation and smoking behaviors and lung cancer risk.
J Natl Cancer Inst. 2011; 103(17):1342-6 [PubMed] Free Access to Full Article Related Publications
Genetic variations in the CYP2A6 nicotine metabolic gene and the CHRNA5-CHRNA3-CHRNB4 (CHRNA5-A3-B4) nicotinic gene cluster have been independently associated with lung cancer. With genotype data from ever-smokers of European ancestry (417 lung cancer patients and 443 control subjects), we investigated the relative and combined associations of polymorphisms in these two genes with smoking behavior and lung cancer risk. Kruskal-Wallis tests were used to compare smoking variables among the different genotype groups, and odds ratios (ORs) for cancer risk were estimated using logistic regression analysis. All statistical tests were two-sided. Cigarette consumption (P < .001) and nicotine dependence (P = .036) were the highest in the combined CYP2A6 normal metabolizers and CHRNA5-A3-B4 AA (tag single-nucleotide polymorphism rs1051730 G>A) risk group. The combined risk group also exhibited the greatest lung cancer risk (OR = 2.03; 95% confidence interval [CI] = 1.21 to 3.40), which was even higher among those who smoked 20 or fewer cigarettes per day (OR = 3.03; 95% CI = 1.38 to 6.66). Variation in CYP2A6 and CHRNA5-A3-B4 was independently and additively associated with increased cigarette consumption, nicotine dependence, and lung cancer risk. CYP2A6 and CHRNA5-A3-B4 appear to be more strongly associated with smoking behaviors and lung cancer risk, respectively.

Blum M, Suzuki A, Ajani JA
A comprehensive review of S-1 in the treatment of advanced gastric adenocarcinoma.
Future Oncol. 2011; 7(6):715-26 [PubMed] Related Publications
Gastric cancer is the fourth most common malignancy worldwide with Japan, Korea, Taiwan, China, Mongolia and many countries in South America and eastern Europe, as well as parts of the Middle East, contributing to the majority of cases. In the USA, it was estimated that approximately 10,620 deaths would be caused by gastric cancer in 2010. Gastric cancer is often diagnosed in its advanced stages. Current first-line treatment for advanced gastric cancer (AGC) using triplet combination chemotherapy containing a platinum-based compound, a fluoropyrimidine with an anthracycline (frequently added in Europe) or a taxane (more often used in the USA and elsewhere) has resulted in higher response rates and modest improvement in overall survival compared with doublet combinations. However, triplet combinations can be associated with increased toxicity compared with the doublets and patient selection becomes important. A desirable research strategy is to improve outcomes of patients with AGC by identifying treatments that are effective, convenient and safe. The interest in oral agents compared with intravenous agents is mounting. One oral fluoropyrimidine, S-1, is novel as it combines tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. S-1 is approved in Japan, China, Taiwan, Korea and Singapore for the treatment of patients with gastric cancer, and more recently has been approved in 27 European countries to treat AGC. Initial clinical trials in the USA and Europe observed diarrhea as the dose-limiting toxicity; however, initial Japanese studies reported myelosuppression as the dose-limiting toxicity. The differing dose tolerance in these two populations is likely due to polymorphisms in the CYP2A6 gene. Based on our review of Phase II and III studies, we conclude that S-1 is a convenient oral fluoropyrimidine that provides safety advantage over intravenous fluorouracil without compromising efficacy against AGC.

Tsunoda A, Nakao K, Watanabe M, et al.
Associations of various gene polymorphisms with toxicity in colorectal cancer patients receiving oral uracil and tegafur plus leucovorin: a prospective study.
Ann Oncol. 2011; 22(2):355-61 [PubMed] Related Publications
BACKGROUND: To assess the predictive value of polymorphism in nine genes, primarily thymidylate synthase (TS) and orotate phosphoribosyltransferase (OPRT), which relates to 5-fluorouracil (5-FU) metabolism, for toxicity in patients treated with oral uracil/tegafur (UFT) plus leucovorin (LV).
PATIENTS AND METHODS: We treated 99 patients with stage II or III colorectal carcinoma with oral UFT + LV. Germline DNA from patients was genotyped for 5-FU and folate metabolism-relating genes. CYP2A6, tegafur-activating enzyme, and uridine diphosphate-glucuronosyltransferase 1A1 genetic variation were also assessed. Toxicity was graded by the National Cancer Institute Common Toxicity Criteria, version 2.0.
RESULTS: The multivariate logistic regression revealed that OPRT 638G>C polymorphism was associated with grade 3 diarrhea [odds ratio (OR) 19.84 for patients with the C/C homozygous type compared with patients with wild type, P = 0.014] and polymorphisms of UGT1A1 were associated with hyperbilirubinemia (OR 38.76 for homozygotes and double heterozygotes of *6 or *28 compared with wild type, P = 0.0008). No relationships were observed between TS polymorphisms and any toxicity.
CONCLUSIONS: OPRT polymorphism predicts toxicity, especially grade 3 or greater diarrhea to oral UFT + LV adjuvant chemotherapy, whereas TS does not, in our study cohort. UGT1A1 polymorphism seems to be a risk factor for hyperbilirubinemia due to UFT+LV.

Canturk P, Caner V, Oruc N, et al.
The mRNA expression of cytochrome P450 isoforms in human gastric tissue.
Hepatogastroenterology. 2010 Mar-Apr; 57(98):372-6 [PubMed] Related Publications
BACKGROUND/AIMS: Human Cytochrome P450 (CYP) comprises a multigene family of microsomal enzymes that metabolize a wide variety of xenobiotics, including drugs and carcinogens. Although the a number of CYP enzymes were also detected in epithelial cells along the gastrointestinal tract, little is known about the expression of CYP genes in gastric tissue.
METHODOLOGY: In this study, the expression patterns of CYP isoforms was investigated in a total of 14 antral biopsy tissues obtained from the patients with either chronic gastritis (n = 6) or cancer (n = 8) by gene-specific real-time reverse transcriptase -PCR analyses. We employed primer sets specific for CYPs -1A1, -1A2, -2A6, -2B6, -2C, -2D6, -2E1, and -3A5.
RESULTS: Among the isoforms CYP1A1, CYP2C and CYP2D6 gave rise to detectable mRNAs in all 14 gastric tissues while the mRNAs for the other CYPs were detected in some of the tissues. The expression patterns were compared to clinical parameters. There were no significant differences in the parameters between the two groups; however the mRNA expression of CYP2A6 was significantly higher in women than man (p < 0.05).
CONCLUSIONS: Our data suggests that the CYP isoforms were independently expressed with respect to the pathological status in human gastric tissue.

Ku CS, Pawitan Y, Sim X, et al.
Genomic copy number variations in three Southeast Asian populations.
Hum Mutat. 2010; 31(7):851-7 [PubMed] Related Publications
Research on the role of copy number variations (CNVs) in the genetic risk of diseases in Asian populations has been hampered by a relative lack of reference CNV maps for Asian populations outside the East Asians. In this article, we report the population characteristics of CNVs in Chinese, Malay, and Asian Indian populations in Singapore. Using the Illumina Human 1M Beadchip array, we identify 1,174 CNV loci in these populations that corroborated with findings when the same samples were typed on the Affymetrix 6.0 platform. We identify 441 novel loci not previously reported in the Database of Genomic Variations (DGV). We observe a considerable number of loci that span all three populations and were previously unreported, as well as population-specific loci that are quite common in the respective populations. From this we observe the distribution of CNVs in the Asian Indian population to be considerably different from the Chinese and Malay populations. About half of the deletion loci and three-quarters of duplication loci overlap UCSC genes. Tens of loci show population differentiation and overlap with genes previously known to be associated with genetic risk of diseases. One of these loci is the CYP2A6 deletion, previously linked to reduced susceptibility to lung cancer.

Canova C, Richiardi L, Merletti F, et al.
Alcohol, tobacco and genetic susceptibility in relation to cancers of the upper aerodigestive tract in northern Italy.
Tumori. 2010 Jan-Feb; 96(1):1-10 [PubMed] Related Publications
AIMS AND BACKGROUND: Each year in Italy there are approximately 14,000 new cases and 7,000 deaths from cancer of the upper aerodigestive tract, which includes malignant tumors originating from the oral cavity, pharynx, larynx and esophagus. Established etiological factors include tobacco consumption and heavy alcohol drinking. The study of single nucleotide polymorphisms in upper aerodigestive tract cancer etiology may help to identify high-risk subgroups and to better understand the pathways leading to the development of these cancers.
METHODS: Italian results on about 500 cases and 500 controls from a large case-control study (ARCAGE) conducted in 10 European countries are presented with the major objectives of updating results on the effects of alcohol and tobacco consumptions in northern Italy, investigating the role of genetic variation with regard to the metabolism of alcohol and carcinogens from tobacco smoke, and evaluating possible interactions of these single nucleotide polymorphisms with these carcinogens.
RESULTS: The present study confirmed the importance of tobacco smoking and alcohol drinking as the main risk factors for upper aerodigestive tract cancers, indicating that about 68% of cancers among populations in northern Italy can be attributed to the combination of these risk factors. Significant associations between metabolizing phase I genes (CYP1A1 and CYP2A6), phase II genes (GSTA2) and upper aerodigestive tract cancers were found. A polymorphism of ADH1C has been associated with an increased risk of upper aerodigestive tract cancers, suggesting that the less rapid alcohol metabolizers are more susceptible to upper aerodigestive tract cancer risk.
CONCLUSIONS: Our results suggest that the ADH1C allele modifies the carcinogenic dose response for alcohol in the upper aerodigestive tract, giving rise to a gene-environment interaction. The role of genes as possible modifiers of life-style risks seems the most reliable.

Thorgeirsson TE, Gudbjartsson DF, Surakka I, et al.
Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior.
Nat Genet. 2010; 42(5):448-53 [PubMed] Free Access to Full Article Related Publications
Smoking is a common risk factor for many diseases. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P < 5 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006).

Ma WJ, Lv GD, Zheng ST, et al.
DNA polymorphism and risk of esophageal squamous cell carcinoma in a population of North Xinjiang, China.
World J Gastroenterol. 2010; 16(5):641-7 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate the role of metabolic enzyme and DNA repair genes in susceptibility of esophageal squamous cell carcinoma (ESCC).
METHODS: A case-control study was designed with 454 samples from 128 ESCC patients and 326 gender, age and ethnicity-matched control subjects. Genotypes of 69 single nucleotide polymorphisms (SNPs) of metabolic enzyme (aldehyde dehydrogenase-2, ALDH2; alcohol dehydrogenase-1 B, ADHB1; Cytochrome P450 2A6, CYP2A6) and DNA repair capacity genes (excision repair cross complementing group 1, ERCC1; O(6)-methylguanine DNA methyltransferase, MGMT; xeroderma pigmentosum group A, XPA; xeroderma pigmentosum group A, XPD) were determined by the Sequenom MassARRAY system, and results were analyzed using unconditional logistic regression adjusted for age, gender.
RESULTS: There was no association between the variation in the ERCC1, XPA, ADHB1 genes and ESCC risk. Increased risk of ESCC was suggested in ALDH2 for frequency of presence C allele of SNP [Rs886205: 1.626 (1.158-2.284)], XPD for C allele [Rs50872: 1.482 (1.058-2.074)], and MGMT for A allele [Rs11016897: 1.666 (1.245-2.228)]. Five variants of MGMT were associated with a protective effect on ESCC carcinogenesis, including C allele [Rs7069143: 0.698 (0.518-0.939)], C allele [Rs3793909: 0.653 (0.429-0.995)], A allele [Rs12771882: 0.719 (0.524-0.986)], C allele [Rs551491: 0.707 (0.529-0.945)], and A allele [Rs7071825: 0.618 (0.506-0.910)]. At the genotype level, increased risk of ESCC carcinogenesis was found in homozygous carriers of the ALDH2 Rs886205 [CC vs TT, odds ratios (OR): 3.116, 95% CI: 1.179-8.234], MGMT Rs11016879 (AA vs GG, OR: 3.112, 95% CI: 1.565-6.181), Rs12771882 (AA vs GG, OR: 2.442, 95% CI: 1.204-4.595), and heterozygotes carriers of the ALDH2 Rs886205 (CT vs TT, OR: 3.930, 95% CI: 1.470-10.504), MGMT Rs11016879 (AG vs GG, OR: 3.933, 95% CI: 2.216-6.982) and Rs7075748 (CT vs CC, OR: 1.949, 95% CI: 1.134-3.350), respectively. Three variants were associated with a protective effect on ESCC carcinogenesis, carriers of the MGMT Rs11016878 (AG vs AA, OR: 0.388, 95% CI: 0.180-0.836), Rs7069143(CT vs CC, OR: 0.478, 95% CI: 0.303-0.754) and Rs7071825 (GG vs AA, OR: 0.493, 95% CI: 0.266-0.915). Increased risk of ESCC metastasis was indicated in MGMT for frequency of presence C allele [Rs7068306: 2.204 (1.244-3.906)], A allele [Rs10734088: 1.968 (1.111-3.484)] and C allele [Rs4751115: 2.178 (1.251-3.791)]. Two variants in frequency of presence C allele of CYP2A6 [Rs8192720: 0.290 (0.099-0.855)] and A allele of MGMT [Rs2053139: 0.511 (0.289-0.903)] were associated with a protective effect on ESCC progression. Increased risk of ESCC metastasis was found in heterozygote carriers of the MGMT Rs7068306 (CG vs CC, OR: 4.706, 95% CI: 1.872-11.833).
CONCLUSION: Polymorphic variation in ALDH2, XPD and MGMT genes may be of importance for ESCC susceptibility. Polymorphic variation in CYP2A6 and MGMT are associated with ESCC metastasis.

Ishii Y, Suzuki S, Takahashi Y, et al.
Can the 2-(13)C-uracil breath test be used to predict the effect of the antitumor drug S-1?
Cancer Chemother Pharmacol. 2010; 66(2):333-43 [PubMed] Related Publications
PURPOSE: S-1 is an oral anticancer drug containing tegafur (FT), a pro-drug of fluorouracil, combined with two modulators, 5-chloro-2,4-dihydroxypyridine and potassium oxonate (Oxo), at a molar ratio of 1:0.4:1. CYP2A6 genetic polymorphism and dihydropyrimidine dehydrogenase (DPD) inhibition are important for the antitumor effect of S-1. Exploiting the usefulness of the 2-(13)C-uracil breath test (UrBT) as an indicator of DPD activity, we examined whether the results of CYP2A6 genetic polymorphism analysis and UrBT could be used to predict the antitumor effect of S-1.
METHODS: Thirty-four patients with advanced or recurrent cancer (15, 16 and 3 with gastric, colorectal and pancreatic cancer, respectively) were orally administered 40 mg/m(2) S-1 twice daily in the morning and evening. Eighteen patients with a complete response (CR)/partial response (PR) (2 with CR, 16 with PR) and 16 with progressive disease (PD) were compared with respect to CYP2A6 genetic polymorphisms (1- vs. 2-allele mutation), UrBT results, and plasma FT and 5-fluorouracil levels at 3 h after S-1 ingestion in the morning.
RESULTS: On multivariate analysis between the CR/PR and PD groups, only the UrBT results was an independent factor of CR/PR to S-1 (95% CI 1.02-1.10).
CONCLUSION: These results suggest that the anticancer effect of S-1 can be predicted by performing UrBT 3 h after the initial oral S-1 administration.

Rodriguez-Antona C, Gomez A, Karlgren M, et al.
Molecular genetics and epigenetics of the cytochrome P450 gene family and its relevance for cancer risk and treatment.
Hum Genet. 2010; 127(1):1-17 [PubMed] Related Publications
The cytochromes P450 (CYPs) are very efficient catalysts of foreign compound metabolism and are responsible for the major part of metabolism of clinically important drugs. The enzymes are important in cancer since they (a) activate dietary and environmental components to ultimate carcinogens, (b) activate or inactivate drugs used for cancer treatment, and (c) are potential targets for anticancer therapy. The genes encoding the CYP enzymes active in drug metabolism are highly polymorphic, whereas those encoding metabolism of precarcinogens are relatively conserved. A vast amount of literature is present where investigators have tried to link genetic polymorphism in CYPs to cancer susceptibility, although not much conclusive data have hitherto been obtained, with exception of CYP2A6 polymorphism and tobacco induced cancer, to a great extent because of lack of important functional polymorphisms in the genes studied. With respect to anticancer treatment, the genetic CYP polymorphism is of greater importance, where treatment with tamoxifen, but also with cyclophosphamide and maybe thalidomide is influenced by CYP genetic variants. In the present review we present updates on CYP genetics, cancer risk and treatment and also epigenetic aspects of interindividual variability in CYP expression and the use of these enzymes as targets for cancer therapy. We conclude that the CYP polymorphism does not predict cancer susceptibility to any large extent but that this polymorphism might be an important factor for optimal cancer therapy using selected anticancer agents.

Rotunno M, Yu K, Lubin JH, et al.
Phase I metabolic genes and risk of lung cancer: multiple polymorphisms and mRNA expression.
PLoS One. 2009; 4(5):e5652 [PubMed] Free Access to Full Article Related Publications
Polymorphisms in genes coding for enzymes that activate tobacco lung carcinogens may generate inter-individual differences in lung cancer risk. Previous studies had limited sample sizes, poor exposure characterization, and a few single nucleotide polymorphisms (SNPs) tested in candidate genes. We analyzed 25 SNPs (some previously untested) in 2101 primary lung cancer cases and 2120 population controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) study from six phase I metabolic genes, including cytochrome P450s, microsomal epoxide hydrolase, and myeloperoxidase. We evaluated the main genotype effects and genotype-smoking interactions in lung cancer risk overall and in the major histology subtypes. We tested the combined effect of multiple SNPs on lung cancer risk and on gene expression. Findings were prioritized based on significance thresholds and consistency across different analyses, and accounted for multiple testing and prior knowledge. Two haplotypes in EPHX1 were significantly associated with lung cancer risk in the overall population. In addition, CYP1B1 and CYP2A6 polymorphisms were inversely associated with adenocarcinoma and squamous cell carcinoma risk, respectively. Moreover, the association between CYP1A1 rs2606345 genotype and lung cancer was significantly modified by intensity of cigarette smoking, suggesting an underlying dose-response mechanism. Finally, increasing number of variants at CYP1A1/A2 genes revealed significant protection in never smokers and risk in ever smokers. Results were supported by differential gene expression in non-tumor lung tissue samples with down-regulation of CYP1A1 in never smokers and up-regulation in smokers from CYP1A1/A2 SNPs. The significant haplotype associations emphasize that the effect of multiple SNPs may be important despite null single SNP-associations, and warrants consideration in genome-wide association studies (GWAS). Our findings emphasize the necessity of post-GWAS fine mapping and SNP functional assessment to further elucidate cancer risk associations.

Ruwali M, Pant MC, Shah PP, et al.
Polymorphism in cytochrome P450 2A6 and glutathione S-transferase P1 modifies head and neck cancer risk and treatment outcome.
Mutat Res. 2009; 669(1-2):36-41 [PubMed] Related Publications
A case control study was carried out to investigate the association of functionally important polymorphism in cytochrome P450 2A6 (CYP2A6) and glutathione S-transferase P1 (GSTP1) genes with head and neck squamous cell carcinoma (HNSCC) and treatment response in cases receiving a combination of chemo-radiotherapy. The study group consisted of 350 males suffering from HNSCC and an equal number of male controls. Multivariate logistic regression analysis revealed statistically significant decrease in risk to HNSCC in cases with variant genotypes (CYP2A6*1B and CYP2A6*4C) of CYP2A6 (OR: 0.78; 95% CI: 0.43-1.22; P=0.04) or GSTP1 (OR: 0.71; 95% CI: 0.51-1.00; P=0.05). The risk associated with these variant genotypes was found to be further decreased in cases carrying a combination of variant genotypes of CYP2A6 and GSTP1 (OR: 0.40; 95% CI: 0.25-0.65; P=0.00). A similar decrease in risk was observed in cases with variant genotypes of CYP2A6 (OR: 0.59; 95% CI: 0.40-0.86; P=0.00) or GSTP1 (OR: 0.62; 95% CI: 0.42-0.91; P=0.01) and who were regular tobacco users (cigarette smokers or tobacco chewers). Interestingly, only 27% of the cases carrying the variant forms of CYP2A6 (*1A/*4C+*1B/*4C+*4C/*4C) responded to the treatment for HNSCC when compared to those with wild-type genotype (69%). However with GSTP1, cases with homozygous mutant genotype (Val/Val) showed a superior treatment response (75%) when compared to cases with wild-type genotype (25%). Further, cases carrying a combination of variant genotype of CYP2A6 and wild-type genotype of GSTP1 exhibited a very poor treatment response demonstrating that polymorphisms in CYP2A6 and GSTP1 not only modified the risk to HNSCC but also played a major role in determining the chemotherapeutic response.

Canova C, Hashibe M, Simonato L, et al.
Genetic associations of 115 polymorphisms with cancers of the upper aerodigestive tract across 10 European countries: the ARCAGE project.
Cancer Res. 2009; 69(7):2956-65 [PubMed] Related Publications
Cancers of the upper aerodigestive tract (UADT) include malignant tumors of the oral cavity, pharynx, larynx, and esophagus and account for 6.4% of all new cancers in Europe. In the context of a multicenter case-control study conducted in 14 centers within 10 European countries and comprising 1,511 cases and 1,457 controls (ARCAGE study), 115 single nucleotide polymorphisms (SNP) from 62 a priori-selected genes were studied in relation to UADT cancer. We found 11 SNPs that were statistically associated with UADT cancers overall (5.75 expected). Considering the possibility of false-positive results, we focused on SNPs in CYP2A6, MDM2, tumor necrosis factor (TNF), and gene amplified in squamous cell carcinoma 1 (GASC1), for which low P values for trend (P trend<0.01) were observed in the main effects analyses of UADT cancer overall or by subsite. The rare variant of CYP2A6 -47A>C (rs28399433), a phase I metabolism gene, was associated with reduced UADT cancer risk (P trend=0.01). Three SNPs in the MDM2 gene, involved in cell cycle control, were associated with UADT cancer. MDM2 IVS5+1285A>G (rs3730536) showed a strong codominant effect (P trend=0.007). The rare variants of two SNPs in the TNF gene were associated with a decreased risk; for TNF IVS1+123G>A (rs1800610), the P trend was 0.007. Variants in two SNPs of GASC1 were found to be strongly associated with increased UADT cancer risk (for both, P trend=0.008). This study is the largest genetic epidemiologic study on UADT cancers in Europe. Our analysis points to potentially relevant genes in various pathways.

Song DK, Xing DL, Zhang LR, et al.
Association of NAT2, GSTM1, GSTT1, CYP2A6, and CYP2A13 gene polymorphisms with susceptibility and clinicopathologic characteristics of bladder cancer in Central China.
Cancer Detect Prev. 2009; 32(5-6):416-23 [PubMed] Related Publications
OBJECTIVE: To explore the association of polymorphisms in N-acetyltransferase 2 (NAT2), glutathione S-transferase (GST), cytochrome P450 (CYP) 2A6, and CYP 2A13 genes with susceptibility and clinicopathologic characteristics of bladder cancer in a Chinese population.
METHODS: In a hospital-based case-control study of 208 cases and 212 controls matched on age and gender, genotypes were determined by PCR-based methods. Risks were evaluated by unconditional logistic regression analysis.
RESULTS: It was found that significant associations of the NAT2 slow-acetylator genotype (odds ratio, OR: 2.42; 95% confidence interval, CI: 1.47-3.99), GSTM1 null genotype (OR: 1.64; 95% CI: 1.11-2.42) and GSTM1/GSTT1-double null genotype (OR: 1.72; 95% CI: 1.00-2.95) with increased risk of bladder cancer. Conversely, carriers with at least one CYP2A6*4 allele showed lower risk than the non-carriers (OR: 0.47; 95% CI: 0.28-0.79). The adjusted ORs (95% CI) for smokers with NAT2 slow-acetylator, GSTM1 null, GSTM1/GSTT1-double null genotype, and variant CYP2A6 genotypes were 2.99 (1.44-6.25), 1.98 (1.13-3.48), 2.66 (1.22-5.81) and 0.41 (0.20-0.86), respectively. Furthermore, NAT2 slow-acetylator, GSTM1 null, and GSTM1/GSTT1-double null genotypes were associated with higher tumor grade (P=0.001, 0.022, and 0.036, respectively), and only NAT2 slow-acetylator genotype was associated with higher tumor stage (P=0.007). CYP2A13 was not associated with risk or tumor characteristics.
CONCLUSION: It is suggested that NAT2 slow-acetylator, GSTM1 null, GSTM1/GSTT1-double null, and variant CYP2A6 genotypes may play important roles in the development of bladder cancer in Henan area, China.

Jeung HC, Rha SY, Park CH, et al.
Copy number changes can be a predictor for hemoglobin reduction after S-1 monotherapy in gastric cancer.
Int J Oncol. 2009; 34(3):787-96 [PubMed] Related Publications
Anemia is a unique side effect in Korean gastric cancer patients after S-1 monotherapy. We studied gastric cancer patients from a phase II trial of S-1 monotherapy with a 2-week treatment and 1-week rest schedule. Patients from a phase II trial of S-1 monotherapy with a 4-week treatment and 2-week rest were used as a reference group. The patients were categorized into two groups based on the degree of hemoglobin reduction per cycle of S-1: the mild reduction group (MRG DeltaHb/cycle < or =1.0) or severe reduction group (SRG DeltaHb/cycle >1.0). DeltaHb/cycle was calculated from maximum reduction of hemoglobin per one cycle of the treatment. Microarray-CGH was performed using a 17K cDNA microarray containing 15,723 unique genes. We selected genes with copy number variation defined as amplification (log2R/G >0.68) or deletion (log2R/G <-0.68), and a genetic aberration frequency difference of > or =30% between the MRG and the SRG. There were no differences in clinical factors, S-1 treatment-related factors (dose, dose intensity), toxicity, S-1 metabolism-related gene copy numbers (CYP2A6, DPD), or progression-free survival between the MRG and the SRG. Three genes were selected from microarray-CGH and logistic regression model: logit LN(Z) = (1.321) + (1.038 x PTX1) + (0.211 x MYO5A) + (0.516 x ZNF664). In the SRG, all 3 genes showed a trend of higher copy numbers than the MRG. There were no common anemia-related genes identified from different chemotherapy schedule of S-1 monotherapy. The logistics obtained from 3 genes predicted the hemoglobin reduction with an accuracy of 78%. The AUC was 0.744 for the final regression model. The combined copy number changes of the 3 genes can be developed into a biomarker in predicting S-1 treatment-related anemia.

Rossini A, de Almeida Simão T, Albano RM, Pinto LF
CYP2A6 polymorphisms and risk for tobacco-related cancers.
Pharmacogenomics. 2008; 9(11):1737-52 [PubMed] Related Publications
Tobacco consumption is the main identifiable risk to cancer, contributing to the majority of tumors in upper aerodigestive tissues. The psychoactive compound responsible for tobacco addiction, nicotine and the potent carcinogens present at high concentrations either in cigarette mainstream smoke or in smokeless tobacco products, 4-(methylnitrosamino)-1-(3-pyridyl)-butanone (NNK) and N-nitrosonornicotine (NNN) can be metabolized by CYP2A6. CYP2A6 is expressed in many aerodigestive tissues with high interindividual variability. The CYP2A6 gene is highly polymorphic and CYP2A6 alleles coding for enzymes with altered expression or metabolic capacity produce alterations in nicotine metabolism in vivo and seem to influence smoking behavior. These polymorphisms may change the rate of NNK and NNN activation and, therefore, may influence cancer risk associated with tobacco consumption. However, to date only a few and inconclusive studies have addressed the risk that a given CYP2A6 polymorphism presents for the development of tobacco-related tumors. Most, but not all, show a reduced risk associated with alleles that result in decreased enzyme activity. The overlapping substrate specificity and tissue expression between CYP2A6 and the highly similar CYP2A13 may add to the conflicting results observed. The intricate regulation of CYP2A6 and the variation of structurally different chemical compounds capable of inhibiting CYP2A enzymes also add to the complexity. Finally, the interaction between polymorphisms of genes that code for CYP2A6, CYP2A13 and other potent carcinogen-metabolizing CYP enzymes may help to determine individuals that are at higher risk of developing tumors associated with tobacco consumption.

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