Relationship Between Polymorphism Of N-acetyltransferase 2 And Genetic Susceptibility To Bladder Cancer

Background and objectiveBladder cancer is the first common cancer in urology. The occurrence of bladder cancer was increasing notably. Smoking tobacco was considered as the important reason inducing bladder cancer. But not all of smokers being with bladder cancer, It suggests the possible difference of individual hereditary susceptibility. The polymorphism of metabolic enzyme of cancerogen is the important foundation of individual hereditary susceptibility. NAT is one of the important phase II metabolism enzymes which catalyse the conjugation of xenobiotics (mainly of aromatic or benzidine) with activated acetyl groups. NAT2 gene which is a polymporphic acetyltransferase gene locus that segreagates individuals into homozygous rapid, heterozygous intermediate and homozygous slow acetylator, which cause different metabolic rates to aromatic carcinogen being relation with some human tumor. Being recently reported, NAT2 slow acetylator can be related with liver cancer and NAT2 rapid acetylator can induce colon carcinoma. But few scholoars reported the polymorphism of NAT2 is relationship with the susceptibility of bladder cancer. In a case-control study, we analysis NAT2 genotypes of bladder cancer in local region. It aims to observe the association with the polymorphism of NAT2 and susceptibility of bladder cancer, in order to screening the crowds with high cancer risk and providing theoretical guidance for prevention and treatment of bladder cancer.Materials and methods1 Subjects Seventy-eight cases of bladder cancer patients from department of urology, the first affiliated hospital of ZhengZhou university from January 2004 to December 2004 were collected. Among them male 54 case, female 24 case, mean age (60.2+16.2). Eighty cases of nontumorous hospital patients(male 63 cases, female 17 cases) were collected. All patients were Chinese han population.2 Epidemiological investigation all patients were investigated by epidemiological questionaire on occupation, environment ,smoking tobacco and materials of tumor.3 NAT2 genotyping Two mililiter venous blood was collected in EDTA-K2 anticoagulant tube. Genomic DNA was extracted by phenol-chloroform method. Polymorphism of NAT2 genotype were analysised by Polymerase chain reaction(PCR), Allele specific polymerase chain reaction (ASPCR) and Restriction fragment length polymorphism (RFLP). Four major acetylator alleles: NAT2*4, NAT2*5(341T-C), NAT2*6(590 G~~A) and NAT2*7(857G^A) were detected. *4/*4 represent homozygous wildtypes; *4/*5, *4/*6 and *4/*7 represent intermediate heterozygous; *5/*5,*5/*6,*5/*7,*6/*6,*6*7 and *7/*7 were homozygous or heterozygous mutants.4 Statistical analysis SPSS 10.0 software package was used in statistical treatment. Chi-square test was used to compare the distribution of NAT2 genotype and single allele in BC group and control group.The relationship between environmental risk factors and bladder cancer was studied by unconditional logistic regressive analysis. An odd ratio(OR) and 95% confidence interval (95%CI)were also calculated .Result1 NAT2 genotype results Four species NAT2 allele were detected among 158 patients. Distribution of NAT2 allele in BC patients: NAT2*4: 56.41%; NAT2*5: 5.13%; NAT2*6: 21.79%; NAT2*7: 12.18%. Distribution of NAT2 allele in controls: NAT2*4: 73.08%; NAT2*5: 3.21%; NAT2*6:10.26%; NAT2*7: 12.18%. Distribution frequency of NAT2 genotype in BC patients: *4/*4, 42.3%; *4/*5, 2.5%; *4/*6, 15.4%; *4/*7, 10.3%; *5/*5, 3.8%; *6/*6, 10.3%; *7/*6, 7.7%; *7/*7, 7.7%. Distribution of NAT2 genotype in control patients: 4/*4, 60.0%; *4/*5, 1.3%; *4/*6, 15.0%; *4/*7, 6.2%;*5/*5, 2.5%; *6/*6, 2.5%; *7/*6, 7.5%; *7/*7, 5.0%.2 Relationship between NAT2 genotype and susceptibility of bladder cancer Distribution of NAT2 slow acetylator is 29.5%(23/78) and 16.7%(13/80) in controls, showing statistically significant difference among two groups of subjects (x2=3.93, P< 0.05).3 Environmental risk factor and bladder cancer Occupational exposure, smoking index were risk factors of bladder cancer, with the odds ratios of 2.67, 2.95 respectively. Gender factor was a protective factor to bladder cancer, with the odds ratio of 0.43.4 Smoking tobacco interaction with NAT2 genotype and association with susceptibility of bladder cancer The distribution of smoker in BC patients is 58.9%(46/78) and 42.3%(33/80) in controls. The difference is significant (x2=4.96, P< 0.05). The distribution of smokers in BC patients group is 32.6%(15/46) and 18.2%(15/46) in controls, showing significant difference (x2=3.96, P<0.05). The distribution of NAT2 slow acetylator between higher smoking index and lower smoking index in two groups has statistically difference.5 Occupational exposure interaction with NAT2 genotype and association with susceptibility of bladder cancer The numbers with occupational exposure in two groups have great difference (x2=3.81, P<0.05), as so as the comparison in NAT2 slow acetylator among occupational exposurers (P<0.05).6 High dose meat intake interaction with NAT2 genotype and association with susceptibility of bladder cancer The comparison of peoples with high dose intake meat and the ratio of NAT2 slow acetylator in two groups have no statistically significant (P>0.05).7 NAT2 genotype and pathological grade The frequency of slow acetylator in bladder cancer between high pathological grade (G2,G3) and low pathological grade (Gl) was significantly different(P<0.05).Conclusion1 Persons with NAT2 slow acetylator have higher cancer risk2 Smoking tobacco and occupational exposure were the susceptible factors of bladdercancer, and high smoking index result in higer cancer risk, meat intaking is no relationship with susceptibility of bladder cancer.3 Except for meat intaking, Smoking tobacco, occupational exposure interaction with NAT2 slow acetyltor increase cancer risk.4 BC patients with NAT2 slow acetylator have high malignant and invasive, unfavourable prognosis.