Association between polymorphisms in the biometabolism genes CYP1A1, GSTM1, GSTT1 and GSTP1 in bladder cancer

Abstract

Numerous enzymes, including Cytochrome P450s (phase I) and Glutathione-S-transferases (phase II), are involved in the metabolic activation and detoxification of carcinogens. Epidemiological studies have consistently demonstrated that bladder cancer is strongly associated with cigarette smoking, and the risk for the development of this neoplasia may be modified by individual differences in carcinogen-metabolizing genes. We investigated the relationship between polymorphisms in the CYP1A1, GSTM1, GSTT1, and GSTP1 genes in a case-control study with 100 bladder cancer patients and 100 controls matched for age, gender, race, and smoking status. The GSTM1, GSTT1, CYP1A1 (A2455-->G), and GSTP1 (A313-->G) genotypes were determined using a multiplex PCR, an allele specific PCR, and a restriction fragment length polymorphism-PCR method. The present case-controlled association study did not detect any positive or negative association for the GSTM1 and GSTP1 genes [odds ratios (OR) = 1.35; 95% confidence interval (CI) = 0.76-2.41 and OR = 0.75; 95% CI = 0.41-1.38, respectively]. Notably, the genes GSTT1 and CYP1A1 exhibited a statistically significant association with bladder cancer (OR = 1.77; 95% CI = 1.01-3.12 and OR = 1.99; 95% CI = 1.07-3.73). No differences for GSTM1 and GSTP1 genotype prevalence between the bladder cancer cases and the controls were observed, however, the null genotype for the GSTT1 gene and the A/G and G/G variants of the CYP1A1 gene may contribute to the development of bladder cancer.

Lack of Association Between CYP1A1 Polymorphisms and Risk of Bladder Cancer: a Meta-analysis

“…The results of meta-regression analyses revealed that sources of heterogeneity were not from any of the factors mentioned above (ethnicity, BC confirmation method, genotyping method, and quality score) in all three genetic models (data not shown). Galbraith plots identified that the study by Grando et al (Grando et al, 2009) was the outlier and main contributor to heterogeneity in the three comparison models (Figure 2). Separate forest plots omitting the outlier study were conducted in each genetic model, the degree of heterogeneity decreased significantly (G vs. A: I 2 = 15.4%, P Q = 0.317; GG+AG vs. AA: I 2 = 0.0%, P Q = 0.437) with the insignificance result remaining the same (G vs. A: OR = 0.92, 95% CI = 0.71-1.18, P = 0.507; GG+AG vs. AA: OR = 0.86, 95% CI = 0.64-1.15, P = 0.305).…”

“…CYP1A1*2B A/G (I1e462Val) and Bladder Cancer Risk: As established above, six studies, with a total of 908 cases and 815 controls, evaluated the association of BC risk in I1e462Val A/G mutation Fontana et al, 2009;Grando et al, 2009;Ozturk et al, 2011;Berber et al, 2013;Fu et al, 2013). According to our results, no significant association between this polymorphism and BC risk was found in all genetic models in the overall populations: i) G vs. A (OR = 1.04, 95% CI = 0.74-1.47, P = 0.810); ii) GG vs. AA (OR = 1.47, 95% CI = 0.70-3.07, P = 0.308); iii) AG vs. AA (OR = 0.97, 95% CI = 0.74-1.27, P = 0.819); iv) GG+AG vs. AA (OR = 1.01, 95% CI = 0.68-1.48, P = 0.970); v) GG vs. AG+AA (OR = 1.45, 95% CI = 0.70-3.02, P = 0.317).…”

“…Data provided by Grando et al (Grando et al, 2009) suggest that the GSTT1 null genotype and the A/G and G/G variants of the CYP1A1 genes may increase the risk for BC. A study by Öztürk et al (Ozturk et al, 2011) also found that the CYP1A1 Ile/Ile (A/A) genotype combined with GSTM1 null genotype may contribute to the development of BC in the Turkish population, and that the CYP1A1Val genotype with GSTM1 null genotype combinations, though not directly associated with risk of BC, is associated with higher grade tumors.…”

“…Manual search of the reference lists did not reveal any additional eligible studies. Thus, eight relevant studies focused on two of the most studied polymorphisms in CYP1A1 (CYP1A1*2B A/G (I1e462Val) and CYP1A1*2A T/C (MspI) and risk of BC were included in our meta-analysis Li et al, 2007;Srivastava et al, 2008;Grando et al, 2009;Fontana et al, 2009;Ozturk et al, 2011;Fu et al, 2013;Berber et al, 2013). Of these, the study by Brockmöller et al identified the relationship between CYP1A1 polymorphisms and BC risk in both alleles, and were therefore treated independently.…”

“…Over 60 carcinogens, including polycyclic aromatic hydrocarbons (PAHs) such as benzo [a]pyrene and aromatic amines, have been identified in cigarette smoke (Luch et al, 2005). These carcinogens, which have been proven to be associated with BC in aluminum workers exposure to PAHs and coal gasification workers exposure to aromatic amines (Boffetta et al, 1997), can be converted, in vivo, into more hydrophilic and chemically active derivatives by the CYP450 enzyme superfamily (Grando et al, 2009).…”