Hisato Inatomi

Effects of glutathione S-transferase (GST) M1 and GSTT1 genotypes on urothelial cancer risk

The M1 member of the mu class of the glutathione S-transferase (GSTM1) gene is present in about 50% of individuals. GSTT1, a member of the theta class, which has been recently shown to be polymorphic, is expressed in 35-90% of individuals. In this study, 145 Japanese patients with urothelial transitional cell carcinoma and 145 healthy controls, frequency-matched for age and gender, were compared for frequencies of GSTM1 and GSTT1 genotypes. The urothelial cancer risk increased due to the GSTM1 null genotype (odds ratio (OR) 1.71, 95% confidence interval (CI) 1.05-2.79). On the other hand, the OR tended to decrease due to the GSTT1 null genotype, although not significantly. Among individuals of the GSTM1 null genotype, those of the GSTT1-positive genotype had a two-fold risk (OR 2.62, 95% CI 1.36-5.05) compared with the GSTT1 null genotype (OR 1.25, 95% CI 0.62-2.51). A significant interaction between the GSTM1 genotype and smoking status was found; the GSTM1 null genotype was associated with an increased risk of urothelial cancer among smokers (OR 1.98, 95% CI 1.10-3.57).

Association of genotypes of carcinogen-activating enzymes, phenol sulfotransferase SULT1A1 (ST1A3) and arylamine N-acetyltransferase NAT2, with urothelial cancer in a Japanese population.

Carcinogenic aromatic amines such as 4‐aminobiphenyl, which is contained in tobacco smoke, are one of the causal factors of urothelial epithelial cancers. 4‐Aminobiphenyl has been shown to be bioactivated through N‐hydroxylation by hepatic cytochrome (CYP) 1A2 and subsequently through O‐sulfation and O‐acetylation by phenol sulfating sulfotransferase, ST1A3 (SULT1A1), and arylamine N‐acetyltransferase, NAT2, respectively. In a case‐control study for urothelial epithelial cancers, low activity alleles of NAT2 are overall high‐risk alleles (OR 2.11; 95% CI 1.08–4.26). Wild‐type ST1A3*1 (213Arg) alleles were slightly overrepresented in nonsmoking urothelial cancer patients (82.6% vs. 69.7%) and in smoking cancer patients (76.7% and 74.3%) compared to a variant ST1A3*2 (213His) allele. In combination of ST1A3 and NAT2 genotypes for analyses of urothelial cancer risk, the highest OR of 2.45 (95% CI 1.04–5.98) was obtained with ST1A3*1 and NAT2 slow genotype among the 4 combinations. Recombinant ST1A3*1 enzyme showed a tendency of catalyzing higher in vitro 3′‐phosphoadenosine 5′‐phosphosulfate‐dependent DNA adduct formation than ST1A3*2 (2.84 ± 0.49 and 2.22 ± 0.11 adducts/108 nucleotides). Combined analyses of different alleles of carcinogenic aromatic amine‐activating phase II enzymes were applied to urothelial cancer risk for the first time and showed the highest risk combination of ST1A3 and NAT2 alleles.

NAT2 GENE POLYMORPHISM AS A POSSIBLE MARKER FOR SUSCEPTIBILITY TO BLADDER CANCER IN JAPANESE

Background : N‐acetyltransferase (NAT) is known to metabolize the carcinogen arylamine. The polymorphism of the NAT2 gene is an important determinant of individual susceptibility to bladder cancer. There are significant interethnic differences in NAT2 allele frequencies. The relationship between NAT2 genotypes and bladder cancer in a Japanese population was investigated.

Significance of Vitamin D Receptor Gene Polymorphism for Risk and Disease Severity of Prostate Cancer and Benign Prostatic Hyperplasia in Japanese

Objective: Recent studies have demonstrated an association between vitamin D receptor (VDR) genotype and prostate cancer. Currently, there is a scarcity of data regarding the association of VDR genotype with benign prostatic hyperplasia (BPH). The purpose of this study was to investigate the TaqI VDR polymorphism in Japanese prostate cancer patients, Japanese BPH patients and Japanese controls in order to determine if an association exists between VDR genotype and the risk of developing prostate cancer and BPH as well as disease severity. Methods: 110 prostate cancer patients, 83 BPH patients and 90 male age-matched controls were genotyped for a previously described TaqI restriction fragment length polymorphism at codon 352 in exon 9 of the VDR gene. Products were digested into T allele or t allele according to the absence or presence of a TaqI restriction site with individuals being classified as TT, Tt or tt. Results: The frequency of the genotype tt was higher in the control group (6.7%) compared to patients with prostate cancer (1.8%) and BPH (3.6%) but this was not statistically significant. However, the frequency of the genotype TT was significantly higher among prostate cancer patients with locally advanced or metastatic disease (T3/ T4/N1/M1) compared to controls (p = 0.001). In addition, the genotype TT was significantly higher among prostate cancer patients with a high Gleason grade of tumor (grade 5) compared to controls (p = 0.0001). In addition, the genotype TT was statistically higher in BPH patients with high prostate volume (volume >50 cm3) compared to controls (p = 0.001). Conclusion: These data demonstrate that VDR genotype plays an important role in determining the risk of more advanced and aggressive prostate cancer as well as prostatic enlargement in Japanese men.

E-cadherin gene polymorphism and risk of urothelial cancer.

The E-cadherin is important in cell-cell adhesion and in the development and maintenance of the epithelial phenotype. A -160C-->A polymorphism in the promoter region of E-cadherin has been shown to decrease gene transcription. This allelic variation may be a potential genetic marker that can help identify those individuals at higher risk for invasive/metastatic disease. We studied the effect of E-cadherin gene polymorphism on urothelial cancer susceptibility in a case control study of 314 urothelial cancer patients and 314 age-sex matched controls, to determine whether this polymorphism is a biomarker for the risk and how aggressive the disease is. The frequency with which the subjects carried E-cadherin A/A genotype was significantly higher in the urothelial cancer patients than in the healthy control subjects (OR=2.32, 95% CI 1.03-5.22). Subdividing urothelial cancer according to tumor differentiation and stage, we found no association between E-cadherin polymorphism and poorly-differentiation and invasiveness of urothelial cancer. Furthermore, no significant association between E-cadherin polymorphism and recurrence rate of urothelial cancer patients was found. The present study demonstrates for the first time that E-cadherin A/A genotype may be associated with susceptibility to urothelial cancer, but not with the progression of disease.

Cytochrome P450 (CYP) 1A2, sulfotransferase (SULT) 1A1, and N-acetyltransferase (NAT) 2 polymorphisms and susceptibility to urothelial cancer

Purpose Arylamines are suspected to be the primary causative agent of urothelial cancer in tobacco smoke. In the human liver, arylamines are N-hydroxylated by a cytochrome P450 (CYP)1A2-catalyzed reaction, which produces a substrate for O-esterification that can be catalyzed by N-acetyltransferases (NAT) or sulfotransferases (SULT). Recently, several polymorphisms of CYP1A2, SULT1A1, and NAT2 that affect their activities have been reported.Methods In this study, 306 Japanese patients with urothelial transitional cell carcinoma and 306 healthy controls were compared for frequencies of CYP1A2, SULT1A1, and NAT2 genotypes.Results The frequencies of NAT2 intermediate or slow acetylator genotype were significantly higher in the urothelial cancer patients than in the healthy control subjects [odds ratio (OR)=1.49, 95% confidence interval (95% CI) 1.06–2.09, OR=3.23, 95% CI 1.72–6.08, respectively]. Stratifying by amount of smoking, among subjects who consumed >33.5 pack-years and carried the SULT1A1 *1/*1 or NAT2 slow acetylator genotype, the OR was 1.73 (95% CI 1.01–2.97) whereas it was 7.31 (95% CI 1.90–28.05) in non-smokers who carried the homozygous wild genotype, respectively. The relationships between CYP1A2, SULT1A1, and NAT2 polymorphisms and clinical findings including tumor differentiation, stage, and recurrence rate were analyzed. Only associations between NAT2 genotype and pathological findings were admitted, and the higher OR of NAT2 intermediate and slow acetylator genotype was more likely to present to a low-grade tumor (G1) among heavy-smokers.Conclusions Our results suggest that SULT1A1 *1/*1 and NAT2 slow acetylator genotypes might modulate the effect of carcinogenic arylamines contained in tobacco smoke, and that the modulation of NAT2 intermediate and slow acetylator genotype has a tendency to present a higher risk for highly differentiated tumors among heavy-smokers.

Lack of Evidence for the Association of E-Cadherin Gene Polymorphism with Increased Risk or Progression of Prostate Cancer

Background: E-cadherin is an epithelial cell adhesion molecule, and decreased E-cadherin expression in human prostate cancer is associated with tumor grade and advanced clinical stage. A –160 C→A polymorphism in the promoter region of E-cadherin has been shown to decrease gene transcription. This allelic variation may be a potential genetic marker that can help identify those individuals at higher risk for invasive/metastatic disease. Materials and Methods: We studied the effect of E-cadherin gene polymorphism on prostate cancer susceptibility in a case control study of 219 prostate cancer patients and 219 male controls, to determine whether this polymorphism is a biomarker for the risk and how aggressive the disease is. Results: The genotype frequencies in the prostate cancer group were C/C: 0.607, C/A: 0.352, A/A: 0.041, and in the control group C/C: 0.671, C/A: 0.301, A/A: 0.027. A significant difference between the two groups was not found (p = 0.34), and the adjusted OR for A/A genotype was not statistically significant (OR = 1.66, 95% CI 0.58–4.78). Subdividing prostate cancer according to tumor differentiation and stage, we found no association between E-cadherin polymorphism and poor differentiation and invasiveness of prostate cancer. Conclusions: These data do not support an association between the E-cadherin genotype and the occurrence or progression of prostate cancer in Japanese populations.

Glutathione S-transferase (GST) M1, T1 and N-acetyltransferase 2 (NAT2) polymorphisms and urothelial cancer risk with tobacco smoking

The objective of this study was to examine the association between the genetic polymorphism of glutathione S-transferase (GST) M1, T1 and N-acetyltransferase 2 (NAT2) genes and urothelial cancer risk in relation to smoking status. In this study, 325 Japanese patients with urothelial transitional cell carcinoma and 325 healthy controls were compared for frequencies of GSTM1, T1 and NAT2 genotypes. The frequencies of GSTM1 null genotype and NAT2 slow genotype were significantly higher in the cases than in the controls (adjusted odds ratio (OR) 1.37, 95% confidence interval (CI) 1.01-1.87, adjusted OR 3.09, 95% CI 1.69-5.63, individually). Furthermore, the risk of GSTM1 null genotype and NAT2 slow genotype was higher among smokers (adjusted OR 1.48, 95% CI 1.01-2.15, adjusted OR 4.28, 95% CI 1.96-9.36, individually). The regression analysis of cancer risk as a function of the amount of smoking showed that the susceptibility of people who had GSTM1 null genotype increased from 45 pack-years, while the susceptibility of people with NAT2 intermediate or slow genotype increased rapidly from 25 pack-years, compared with non-smokers. A multiplicative interaction between NAT2 intermediate or slow genotype and pack-years of smoking was found (P<0.001), but GSTM1 null genotype was not (P=0.06). Our results indicate that the GSTM1 null genotype and NAT2 intermediate or slow genotype are associated with an increased risk of urothelial cancer in relation to smoking amounts. Furthermore, the interaction between NAT2 intermediate or slow genotype and pack-years of smoking has a strong impact on urothelial cancer.

Results of conservative treatment of upper urinary tract transitional cell carcinoma.

Background : The treatment preserving the kidney for upper urinary tract tumor is still controversial. The indications and results of conservative treatment remain to be elucidated. Experiences of this type of treatment are reported.

Diagnosis of Retrovesical Ectopic and Hyperplastic Prostate Tissue by Transrectal Needle Biopsy

We report on an ectopic prostate in a 50-year-old man. Transabdominal ultrasonography, pelvic computed tomography, and pelvic magnetic resonance imaging revealed a heterogeneous tumor 8 cm in diameter in contact with the posterior wall of the urinary bladder. The tumor was histologically confirmed to be a benign prostatic hyperplasia. This is the 3rd case of retrovesical ectopic prostatic tissue which was diagnosed by transrectal needle biopsy.