Abstract
Purpose: Polycyclic aromatic hydrocarbons are activated by cytochrome P450 1A1 (CYP1A1) and inactivated by glutathione S-transferase mu (GSTM1). Therefore, it is expected that a combination of proficient CYP1A1 genotype with deficient GSTM1 variant would result in particularly elevated lung cancer (LC) risk, especially for squamous cell carcinoma (SCC). This study was aimed to validate whether the CYP1A1-C 3801 (CYP1A1*2) allele has an unfavorable significance alone and/or in combination with the GSTM1 deficiency. Methods: We compared the distribution of CYP1A1 and GSTM1 genotypes in LC patients (n=141), healthy donors (HD, n=204), and elderly tumor-free smokers and non-smokers (ED, n=246). Results: CYP1A1*2 allele carriers demonstrated a clear-cut association with SCC: the adjusted odds ratios (OR) were 2.22 (95% CI=1.06–4.63) and 2.27 (95% CI=1.14–4.52) when HD and ED were used as referents, respectively. CYP1A1*2(+)/GSTM1(-) combined genotypes were overrepresented in the SCC patients (14/70, 20.0%) and underrepresented in the ED (19/246, 7.7%) as compared to the intermediate prevalence in the HD (26/204, 12.7%); the adjusted OR for SCC versus ED reached 3.85 (95% CI=1.43–10.33). Conclusions: In agreement with some literature data, our results support the concerted role of CYP1A1 and GSTM1 at-risk genotypes in SCC predisposition.
Keywords: CYP1A1, GSTM1, Lung cancer, Predisposition, Elderly
Introduction
Lung cancer (LC) risk has long been suspected to be modified by variations in the individual capacity to activate and/or detoxify inhaled carcinogenic compounds. Studies on genetic polymorphisms of enzymes responsible for the metabolism of xenobiotics have revealed several candidates as LC-predisposing alleles. However, the contribution of any single enzyme appears to be prohibitively small to bear any medical significance (Kiyohara et al. 2002; Imyanitov et al. 2004, Imyanitov et al. 2005), because its impact is likely to be compensated by other members of the same metabolic pathway. Therefore, only a combination of complementary gene polymorphisms may exert a noticeable predictive value (Fryer and Jones 1999). The most frequently cited example in this context refers to the concerted action of two polymorphic participants of metabolism of polycyclic aromatic hydrocarbons (PAH), i.e., cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase mu (GSTM1) (Vineis et al. 2004). The CYP1A1 enzyme possesses aryl hydrocarbon hydroxylase activity, which plays a role in the carcinogenic activation of PAH. Increased metabolic capacity of CYP1A1 is often associated with the so-called CYP1A1*2 alleles (www.imm.ki.se/CYPalleles/cyp1a1.htm), which contain either or both of the two closely linked substitutions, T3801C and A2455G (Hirvonen 2004). In contrast to CYP1A1, the GSTM1 enzyme deactivates the carcinogenic PAH metabolites; approximately a half of Caucasians are deficient for GSTM1 due to deletion of the gene (Fryer and Jones 1999; Bartsch et al. 2000).
It is expected that the combination of proficient CYP1A1 genotype with the deficient GSTM1 variant would result in particularly elevated LC risk. This hypothesis was confirmed in now-classical Japanese studies, which demonstrated only a modest LC-predisposing effect for the unfavorable CYP1A1 or GSTM1 variants alone, but evident association with the malignant disease for the combined CYP1A1/GSTM1 at-risk genotype (Hayashi et al. 1992; Nakachi et al. 1993; Kihara et al. 1995). Several factors, however, complicate the validation of the gene–gene interaction between the CYP1A1 and GSTM1. Ethnic variations appear to be important in this instance: Caucasians represent a difficult racial group for the analysis of CYP1A1/GSTM1 combinations, owing to the lower populational occurrence of CYP1A1 at-risk alleles when compared to Orientals (Vineis et al. 2003). Furthermore, the heterogeneity of LC may contribute to inconsistency; the PAH exposure appears to specifically increase the risk of developing squamous cell carcinoma (SCC) of the lung, whereas its predisposing effect is less obvious in the case of other histological types of LC (Hecht 1997). In agreement with this view, the overrepresentation of the unfavorable combination of CYP1A1/GSTM1 genotypes was recorded primarily in SCC cases but not in other forms of LC (Le Marchand et al. 1998).
Our earlier investigations, employing a novel study design, which involved an additional “cancer-tolerant” reference group consisting of elderly tumor-free smokers and non-smokers, supported the view that the GSTM1-null genotype poses a modest increase in the risk for SCC of the lung (Belogubova et al. 2004). Here we extended the study to evaluate if the CYP1A1 polymorphism, either alone or in combination with the GSTM1 polymorphism, played any significant role in this context.
Materials and methods
The mode of subject selection, the GSTM1 genotyping method and the statistical procedures have been described in detail in Belogubova et al. (2004). Briefly, 141 LC patients (mean age: 60.6 years; age range: 29–84 years) were incident histologically confirmed cases diagnosed in the N.N. Petrov Institute, St.-Petersburg, Russia; half (70) of the patients had SCC while the rest (71) had other histological types of LC. 204 healthy donors (HD) were middle-aged subjects (mean age: 35.6 years; age range: 18–55) recruited in the blood transfusion unit located in the same Institute. Elderly tumor-free smokers and non-smokers (“elderly donors”, ED; n=246; mean age: 79.3 years; age range: 75–95) were collected in the general hospitals of St.-Petersburg. Thus all patients and donors were from the same catchment area and represented a relatively homogenous population of Caucasians of Russian origin. DNA was isolated from peripheral blood cells of the study subjects using standard techniques. Detection of the T3801C base change (NCBI SNP database: rs4646903) was performed essentially as in Hayashi et al. (1991); the 3801C carrying alleles were hereof designated as CYP1A1*2 in accordance with Garte and Crosti (1999). Statistical comparisons were done by calculating crude and adjusted odds ratios (OR) and 95% confidence intervals (CI).
Results and discussion
The distribution of GSTM1 and CYP1A1 genotypes in LC patients, HD and elderly tumor-free subjects is described in Table 1 and summarized in Table 2. Both GSTM1-null and CYP1A1*2 allele containing genotypes tended to be overrepresented in patients with squamous cell type of lung carcinoma. The difference for GSTM1 was approaching close to the formal level of statistical significance only when elderly subjects served as a control (Table 3). In contrast to the marginal effect of the GSTM1 deficiency, CYP1A1*2 allele carriers demonstrated a clear-cut association with SCC [25/70 (35.7%) in SCC patients; 12/71 (16.9%) in non-SCC LC cases; 43/204 (21.1%) in HD; 50/246 (20.3%) in ED] (Table 2); the adjusted OR were 2.22 (95% CI=1.06–4.63) and 2.27 (95% CI=1.14–4.52) when HD and ED were used as referents, respectively (Table 3). When the combined genotypes were considered, the prevalence of the putatively most favorable combination, i.e., concurrent presence of the CYP1A1*1/*1 and the GSTM1 positive genotype, was highest in the “cancer-tolerant” ED (106/246, 43.1%), intermediate in the HD (77/204, 37.7%), and lowest in the LC patients (49/141, 34.8%), especially in SCC cases (20/70, 28.6%) (Table 2). Furthermore, the presumably most unfavorable genotype combination, i.e., concurrent presence of the CYP1A1*2 allele carrying genotypes and the GSTM1-null genotype, was overrepresented in the SCC patients (14/70, 20.0%) and underrepresented in the ED (19/246, 7.7%) as compared to the intermediate prevalence in the HD (26/204, 12.7%) (Table 2). This genotype combination posed a remarkably increased risk of SCC when analyzed against ED (OR=3.85, 95% CI=1.43–10.33) (Table 3). As seen in the Tables 2 and 3, the degree of combined effect of GSTM1 and CYP1A1 at-risk variants was in good concordance with the contribution of individual genotypes; the lack of interaction between GSTM1 and CYP1A1 alleles was confirmed by logistic regression analysis.
Table 1.
Distribution of GSTM1 and CYP1A1 genotypes in the study populations
| Groups | GSTM1 genotypesa (%) | CYP1A1 genotypes (%) | Combined GSTM1/CYP1A1 genotypes (%) | Total | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| GSTM1(+) | GSTM1(-) | CYP1A1*1/*1 | CYP1A1*1/*2 | CYP1A1*2/*2 | GSTM1(+) CYP1A1*1/*1 | GSTM1 (-) CYP1A1*1/*1 | GSTM1(+) CYP1A1 *1/*2 | GSTM1(-) CYP1A1 *1/*2 | GSTM1(+) CYP1A1 *2/*2 | GSTM1(-) CYP1A1 *2/*2 | ||
| Elderly donors (ED) | 137 (55.7) | 109 (44.3) | 196 (79.7) | 49 (19.9) | 1 (0.4) | 106 (43.1) | 90 (36.6) | 31 (12.6) | 18 (7.3) | – | 1 (0.4) | 246 (100) |
| Smokers | 58 (57.4) | 43 (42.6) | 81 (80.2) | 20 (19.8) | – | 48 (47.5) | 33 (32.7) | 10 (9.9) | 10 (9.9) | – | – | 101 (100) |
| Men | 51 (58.0) | 37 (42.0) | 70 (79.5) | 18 (20.5) | – | 41 (46.6) | 29 (33.0) | 10 (11.4) | 8 (9.1) | – | – | 88 (100) |
| Women | 7 (53.8) | 6 (46.2) | 11 (84.6) | 2 (15.4) | – | 7 (53.8) | 4 (30.8) | – | 2 (15.4) | – | – | 13 (100) |
| Non-smokers | 79 (54.5) | 66 (45.5) | 115 (79.3) | 29 (20.0) | 1 (0.7) | 58 (40.0) | 57 (39.3) | 21 (14.5) | 8 (5.5) | – | 1 (0.7) | 145 (100) |
| Men | 19 (47.5) | 21 (52.5) | 33 (82.5) | 7 (17.5) | – | 14 (35.0) | 19 (47.5) | 5 (12.5) | 2 (5.0) | – | – | 40 (100) |
| Women | 60 (57.1) | 45 (42.9) | 82 (78.1) | 22 (21.0) | 1 (1.0) | 44 (41.9) | 38 (36.2) | 16 (15.2) | 6 (5.7) | – | 1 (1.0) | 105 (100) |
| Total ED men | 70 (54.7) | 58 (45.3) | 103 (80.5) | 25 (19.5) | – | 55 (43.0) | 48 (37.5) | 15 (11.7) | 10 (7.8) | – | – | 128 (100) |
| Total ED women | 67 (56.8) | 51 (43.2) | 93 (78.8) | 24 (20.3) | 1 (0.8) | 51 (43.2) | 42 (35.6) | 16 (13.6) | 8 (6.8) | – | 1 (0.8) | 118 (100) |
| Middle-aged donors (HD) | 94 (46.1) | 110 (53.9) | 161 (78.9) | 41 (20.1) | 2 (1.0) | 77 (37.7) | 84 (41.2) | 17 (8.3) | 24 (11.8) | – | 2 (1.0) | 204 (100) |
| Smokers | 56 (42.4) | 76 (57.6) | 107 (81.1) | 24 (18.2) | 1 (0.8) | 49 (37.1) | 58 (43.9) | 7 (5.3) | 17 (12.9) | – | 1 (0.8) | 132 (100) |
| Men | 33 (48.5) | 35 (51.5) | 54 (79.4) | 13 (19.1) | 1 (1.5) | 29 (42.6) | 25 (36.8) | 4 (5.9) | 9 (13.2) | – | 1 (1.5) | 68 (100) |
| Women | 23 (35.9) | 41 (64.1) | 53 (82.8) | 11 (17.2) | – | 20 (31.3) | 33 (51.6) | 3 (4.7) | 8 (12.5) | – | – | 64 (100) |
| Non-smokers | 38 (52.8) | 34 (47.2) | 54 (75.0) | 17 (23.6) | 1 (1.4) | 28 (38.9) | 26 (36.1) | 10 (13.9) | 7 (9.7) | – | 1 (1.4) | 72 (100) |
| Men | 11 (50.0) | 11 (50.0) | 16 (72.7) | 5 (22.7) | 1 (4.5) | 10 (45.5) | 6 (27.3) | 1 (4.5) | 4 (18.2) | – | 1 (4.5) | 22 (100) |
| Women | 27 (54.0) | 23 (46.0) | 38 (76.0) | 12 (24.0) | – | 18 (36.0) | 20 (40.0) | 9 (18.0) | 3 (6.0) | – | – | 50 (100) |
| Total HD men | 44 (48.9) | 46 (51.1) | 70 (77.8) | 18 (20.0) | 2 (2.2) | 39 (43.3) | 31 (34.4) | 5 (5.6) | 13 (14.4) | – | 2 (2.2) | 90 (100) |
| Total HD women | 50 (43.9) | 64 (56.1) | 91 (79.8) | 23 (20.2) | – | 38 (33.3) | 53 (46.5) | 12 (10.5) | 11 (9.6) | – | – | 114 (100) |
| Lung cancer (LC) patients | 67 (47.5) | 74 (52.5) | 104 (73.8) | 35 (24.8) | 2 (1.4) | 49 (34.8) | 55 (39.0) | 17 (12.1) | 18 (12.8) | 1 (0.7) | 1 (0.7) | 141 (100) |
| Smokers | 60 (48.4) | 64 (51.6) | 91 (73.4) | 31 (25.0) | 2 (1.6) | 44 (35.5) | 47 (37.9) | 15 (12.1) | 16 (12.9) | 1 (0.8) | 1 (0.8) | 124 (100) |
| Men | 59 (49.6) | 60 (50.4) | 87 (73.1) | 30 (25.2) | 2 (1.7) | 43 (36.1) | 44 (37.0) | 15 (12.6) | 15 (12.6) | 1 (0.8) | 1 (0.8) | 119 (100) |
| Women | 1 (20.0) | 4 (80.0) | 4 (80.0) | 1 (20.0) | – | 1 (20.0) | 3 (60.0) | – | 1 (20.0) | – | – | 5 (100) |
| Non-smokers | 7 (41.2) | 10 (58.8) | 13 (76.5) | 4 (23.5) | – | 5 (29.4) | 8 (47.1) | 2 (11.8) | 2 (11.8) | – | – | 17 (100) |
| Men | 2 (40.0) | 3 (60.0) | 4 (80.0) | 1 (20.0) | – | 2 (40.0) | 2 (40.0) | – | 1 (20.0) | – | – | 5 (100) |
| Women | 5 (41.7) | 7 (58.3) | 9 (75.0) | 3 (25.0) | – | 3 (25.0) | 6 (50.0) | 2 (16.7) | 1 (8.3) | – | – | 12 (100) |
| NSCLC | 58 (47.5) | 64 (52.5) | 88 (72.1) | 32 (26.2) | 2 (1.6) | 41 (33.6) | 47 (38.5) | 16 (13.1) | 16 (13.1) | 1 (0.8) | 1 (0.8) | 122 (100) |
| SCC | 31 (44.3) | 39 (55.7) | 45 (64.3) | 23 (32.9) | 2 (2.9) | 20 (28.6) | 25 (35.7) | 10 (14.3) | 13 (18.6) | 1 (1.4) | 1 (1.4) | 70 (100) |
| ADC | 18 (58.1) | 13 (41.9) | 27 (87.1) | 4 (12.9) | – | 14 (45.2) | 13 (41.9) | 4 (12.9) | – | – | – | 31 (100) |
| Other NSCLC types | 9 (42.9) | 12 (57.1) | 16 (76.2) | 5 (23.8) | – | 7 (33.3) | 9 (42.9) | 2 (9.5) | 3 (14.3) | – | – | 21 (100) |
| SCLC | 9 (47.4) | 10 (52.6) | 16 (84.2) | 3 (15.8) | – | 8 (42.1) | 8 (42.1) | 1 (5.3) | 2 (10.5) | – | – | 19 (100) |
| Age ≤?50 years | 4 (28.6) | 10 (71.4) | 12 (85.7) | 2 (14.3) | – | 2 (14.3) | 10 (71.4) | 2 (14.3) | – | – | – | 14 (100) |
| Age > 50 years | 63 (49.6) | 64 (50.4) | 92 (72.4) | 33 (26.0) | 2 (1.6) | 47 (37.0) | 45 (35.4) | 15 (11.8) | 18 (14.2) | 1 (0.8) | 1 (0.8) | 127 (100) |
| Total LC men | 61 (49.2) | 63 (50.8) | 91 (73.4) | 31 (25.0) | 2 (1.6) | 45 (36.3) | 46 (37.1) | 15 (12.1) | 16 (12.9) | 1 (0.8) | 1 (0.8) | 124 (100) |
| Total LC women | 6 (35.3) | 11 (64.7) | 13 (76.5) | 4 (23.5) | – | 4 (23.5) | 9 (52.9) | 2 (11.8) | 2 (11.8) | – | – | 17 (100) |
aGSTM1 genotypes are designated as GSTM1(-) for the null and GSTM1(+) for the non-null
Table 2.
Summary of the frequencies of favorable and unfavorable GSTM1 and CYP1A1 genotypes in the study populations
| Groups | GSTM1 genotypesa (%) | CYP1A1 genotypes (%) | Combined GSTM1/CYP1A1 genotypes (%) | Total | |||||
|---|---|---|---|---|---|---|---|---|---|
| GSTM1(+) | GSTM1(-) | CYP1A1*2 non-carriers | CYP1A1*2 carriers | GSTM1(+) CYP1A1*2 non-carriers | GSTM1(-) CYP1A1*2 non-carriers | GSTM1(+) CYP1A1*2 carriers | GSTM1(-) CYP1A1*2 carriers | ||
| ED | 137 (55.7) | 109 (44.3) | 196 (79.7) | 50 (20.3) | 106 (43.1) | 90 (36.6) | 31 (12.6) | 19 (7.7) | 246 (100) |
| HD | 94 (46.1) | 110 (53.9) | 161 (78.9) | 43 (21.1) | 77 (37.7) | 84 (41.2) | 17 (8.3) | 26 (12.7) | 204 (100) |
| All LC patients | 67 (47.5) | 74 (52.5) | 104 (73.8) | 37 (26.2) | 49 (34.8) | 55 (39.0) | 18 (12.8) | 19 (13.5) | 141 (100) |
| SCC LC patients | 31 (44.3) | 39 (55.7) | 45 (64.3) | 25 (35.7) | 20 (28.6) | 25 (35.7) | 11 (15.7) | 14 (20.0) | 70 (100) |
| Non-SCC LC patients | 36 (50.7) | 35 (49.3) | 59 (83.1) | 12 (16.9) | 29 (40.9) | 30 (42.3) | 7 (9.9) | 5 (7.0) | 71 (100) |
aGSTM1 genotypes are designated as GSTM1(-) for the null and GSTM1(+) for the non-null
Table 3.
Analysis of associations between GSTM1 and CYP1A1 genotypes and LC risk: crude and adjusted odds ratios and 95% confidence intervals
| Groups | GSTM1 genotypesa | CYP1A1 genotypes | Combined GSTM1/CYP1A1 genotypes | |||||
|---|---|---|---|---|---|---|---|---|
| GSTM1(+) | GSTM1(-) | CYP1A1*2 non-carriers | CYP1A1*2 carriers | GSTM1(+) CYP1A1*2 non-carriers | GSTM1(-) CYP1A1*2 non-carriers | GSTM1(+) CYP1A1*2 carriers | GSTM1(-) CYP1A1*2 carriers | |
| Crude ORs | ||||||||
| LC versus HD | 1.0 | 0.94 (0.61–1.45) | 1.0 | 1.33 (0.80–2.21) | 1.0 | 1.03 (0.63–1.69) | 1.66 (0.78–3.57) | 1.15 (0.57–2.30) |
| LC versus ED | 1.0 | 1.39 (0.92–2.11) | 1.0 | 1.39 (0.85–2.27) | 1.0 | 1.32 (0.82–2.13) | 1.26 (0.63–2.46) | 2.16 (1.04–4.47) |
| SCC versus HD | 1.0 | 1.08 (0.62–1.87) | 1.0 | 2.08 (1.14–3.76) | 1.0 | 1.15 (0.59–2.25) | 2.49 (0.98–6.16) | 2.07 (0.90–4.69) |
| SCC versus ED | 1.0 | 1.58 (0.92–2.71) | 1.0 | 2.18 (1.21–3.88) | 1.0 | 1.47 (0.76–2.85) | 1.88 (0.79–4.32) | 3.91 (1.65–9.06) |
| Non-SCC versus HD | 1.0 | 0.83 (0.48–1.43) | 1.0 | 0.76 (0.36–1.52) | 1.0 | 0.95 (0.52–1.73) | 1.09 (0.39–2.88) | 0.51 (0.16–1.41) |
| Non-SCC versus ED | 1.0 | 1.22 (0.72–2.08) | 1.0 | 0.80 (0.39–1.57) | 1.0 | 1.22 (0.68–2.19) | 0.83 (0.31–2.02) | 0.96 (0.30–2.71) |
| ORs adjusted for gender and smoking history | ||||||||
| LC versus HD | 1.0 | 1.13 (0.68–1.87) | 1.0 | 1.27 (0.70–2.30) | 1.0 | 1.33 (0.75–2.37) | 2.06 (0.79–5.41) | 1.20 (0.54–2.65) |
| LC versus ED | 1.0 | 1.54 (0.96–2.48) | 1.0 | 1.37 (0.78–2.40) | 1.0 | 1.58 (0.92–2.71) | 1.43 (0.65–3.15) | 2.08 (0.92–4.73) |
| SCC versus HD | 1.0 | 1.25 (0.65–2.41) | 1.0 | 2.22 (1.06–4.63) | 1.0 | 1.51 (0.69–3.30) | 3.99 (1.11–14.32) | 2.21 (0.84–5.77) |
| SCC versus ED | 1.0 | 1.79 (0.96–3.35) | 1.0 | 2.27 (1.14–4.52) | 1.0 | 1.78 (0.84–3.78) | 2.25 (0.82–6.19) | 3.85 (1.43–10.33) |
| Non-SCC versus HD | 1.0 | 0.97 (0.54–1.73) | 1.0 | 0.72 (0.34–1.55) | 1.0 | 1.17 (0.61–2.24) | 1.33 (0.44–4.06) | 0.53 (0.17–1.59) |
| Non-SCC versus ED | 1.0 | 1.32 (0.75–2.30) | 1.0 | 0.80 (0.38–1.66) | 1.0 | 1.41 (0.76–2.61) | 0.96 (0.36–2.55) | 0.92 (0.30–2.82) |
aGSTM1 genotypes are designated as GSTM1(-) for the null and GSTM1(+) for the non-null
Taken together, our results point at the unfavorable effect of the CYP1A1*2 allele in the development of SCC of the lung. Furthermore, this study supports the combined effect of GSTM1 and CYP1A1 at-risk alleles (Vineis et al. 2004), which is proven not only by the increased prevalence of their combinations in SCC patients, but also by the depletion of the CYP1A1*2(+)/GSTM1(-) variants in those subjects who succeeded to achieve an elderly age without history of neoplastic disease.
Acknowledgements
We are grateful to Prof. Vladimir G. Lemehov for providing clinical expertize. We also thank Mrs. Olga S. Yatsuk, Olga A. Zaitseva and Liudmila V. Rikunova for the technical assistance. The work was supported by INTAS (grant 99–01391) and RFBR (grant 02–04–49794)
Abbreviations
- LC
Lung cancer
- SCC
Squamous cell carcinoma
- HD
Healthy donors
- ED
Elderly donors
- OR
Odds ratio
- CI
Confidence interval
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