Human Molecular Genetics, 2001, Vol. 10, No. 12 1265-1273
© 2001 Oxford University Press
Genetic polymorphisms of biotransformation enzymes in patients with Hodgkin’s and non-Hodgkin’s lymphomas
Biotransformations Group, Center of Occupational Diseases, National Institute of Public Health, Srobárova 48, Praha 10, 100 42, Czech Republic, 11st Department of Internal Medicine, University Hospital, U nemocnice 2, Praha 2, 128 08, Czech Republic and 2Department of Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Montebello 0310, Oslo, Norway
Received 12 January 2001; Revised and Accepted 3 April 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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Considering the role in the metabolism of chemicals played by biotransformation enzymes, we aimed at determining whether any association exists between genetic polymorphisms in CYP1A1, CYP2E1, epoxide hydrolase (EPHX), glutathione S-transferases (GSTM1/P1/T1) and individual susceptibility to lymphomas. PCR–RFLP-based genotyping assays were used to determine the frequency of polymorphisms in CYP1A1 (3'-flanking region), CYP2E1 (5'-flanking region and intron 6), EPHX (exons 3 and 4), GSTM1 (deletion), GSTP1 (exon 5) and GSTT1 (deletion) in a case-control study comprised of 219 patients with morbus Hodgkin (MH) and non-Hodgkin’s lymphomas (NHL) and 455 age- and sex-matched healthy individuals. The distribution of genotypes in CYP2E1-intron 6 was significantly different between the control group and all lymphomas (P = 0.03), patients with NHL (P = 0.024), and especially aggressive diffuse NHL (P = 0.007). Grading of NHL seemed to be associated with this polymorphism as well (P = 0.041). The EPHX-exon 3 genotype distribution was significantly different between control males and males with all lymphomas (P = 0.01) or with NHL (P = 0.019). The Val/Val genotype of GSTP1-exon 5 was prevalent in all MH [odds ratio (OR) = 2.08, 95% confidence interval (CI) = 1.05–4.14] and this difference was particularly evident in females (OR = 2.97, 95% CI = 1.16–7.61). A significant difference in the distribution of GSTP1-exon 5 genotypes was found between NHL tumors >5 cm and those <5 cm (P = 0.03). The results suggest that genetic polymorphisms of biotransformation enzymes may play a significant role in the development of lymphoid malignancies.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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The genetically variable biotransformation enzymes, cytochromes P450 (CYP, EC 1.14.14.1), epoxide hydrolase (EPHX, EC 3.3.2.3), and glutathione S-transferases (GST, EC 2.5.1.18) metabolize drugs, carcinogens and natural products (1). In addition, most probably
90% of human cancers result from exposure to environmental carcinogens (2) suggesting that individual effectiveness in the detoxification of these chemicals may influence susceptibility to malignant disease. CYP1A1 catalyzes the oxidation of polycyclic aromatic hydrocarbons (PAHs) to epoxides and is inducible by PAH. The polymorphic CYP1A1 is located on chromosome 15 (15q22–q24) and its genetic polymorphism in the 3'-flanking region (MspI site) was associated with increased inducibility of CYP1A1 in some studies and with the elevated risk of lung cancer (3–6) and colorectal cancer (7) in Oriental populations. On the contrary, the majority of studies on Caucasian patients did not confirm the association of this polymorphism with lung cancer (8–11). The frequency of variant allele m2 was higher in breast cancer patients of Afro-American origin (12).
CYP2E1 is inducible by ethanol and metabolizes a variety of nitrosamines and low molecular weight chemicals (13). Two polymorphic sites of CYP2E1, located on chromosome 10 (10q24.3), are the most studied with the 5'-flanking region (RsaI site) and the intron 6 (DraI site) polymorphism (14,15). Both CYP2E1 variant alleles (RsaI, allele c2; DraI, allele C) have been linked with increased risk of lung cancer in Caucasians and Orientals (16–18) and of nasopharyngeal cancer (19).
EPHX catalyzes the hydrolysis of both aromatic and aliphatic epoxides to less reactive trans-dihydrodiols (20). The absence of genetic complexity of EPHX, located on chromosome 1 (1p11), is in striking contrast to other biotransformation enzymes (CYPs, GSTs, NATs) (21). Two common aberrant alleles of EPHX can be detected by their mutations in exon 3 (EcoRV site, Tyr/His) and exon 4 (RsaI site, His/Arg), which confer slow and fast enzyme activity, respectively (21). Smith and Harrison (22) found that slow EPHX phenotype, assessed by genotyping, was four to five times more common in groups of patients suffering from chronic obstructive pulmonary disease and emphysema. Benhamou et al. (23) reported a significant association between EPHX-exon 3 genotype frequencies, estimated EPHX activity and lung cancer.
GSTs are responsible for the detoxification of many carcinogens (24). GSTM1 is located on chromosome 1 (1p13.3) and recent meta-analysis of epidemiological studies showed that GSTM1 deficiency caused by homozygous deletion of the gene (null genotype) confers an increased risk of lung cancer (25). Another gene deletion at the GSTT1 locus (22q12) was reported by Pemble et al. (26). The biological consequences of failure to express functional GSTM1 and GSTT1 protein can also include susceptibility to cancer of bladder, colon, skin and stomach (27,28).
GSTP1, located on chromosome 11 (11q13), encodes the major enzyme involved in the inactivation of tobacco-related procarcinogens. Board (29) identified two GSTP1 polymorphisms in exon 5 (Ile/Val in codon 105) and exon 6 (Ala/Val in codon 114). It was shown that the GSTP1 allelic variants generate enzymes with different heat stabilities and substrate affinities (30). GSTP1 is overexpressed in some tumors and drug-resistant cell lines which may imply its role as a significant factor in acquired resistance to certain anticancer drugs (27). Results of Park et al. (31) suggest that the GSTP1 genotype may play a role in oral cancer risk, particularly among lighter smokers. In the study of Ryberg et al. (32) the frequency of Val/Val genotype in exon 5 of GSTP1 was significantly higher in lung cancer patients compared with healthy control individuals.
Both Hodgkin’s (MB) and non-Hodgkin’s lymphomas (NHLs) constitute a diverse group of malignancies with respect to histology, clinical presentation and disease progression.
Lymphoma development has been linked with exposure to a variety of chemicals, including nitrates, pesticides, herbicides and solvents (33,34). Much current interest centers on the possibility that environmental benzene exposure in the general public may underline a proportion of the increase in NHL (35). Benzene exposure is common and almost every person in urban locations may be considered as exposed (causes include vehicle exhaust emissions, active and passive smoking and petrochemical products from industrial and household sources).
Our study aimed at determining whether any association exists between the main genetic polymorphisms in enzymes metabolizing environmental contaminants (including benzene), CYP1A1, CYP2E1, EPHX and GSTs, and individual susceptibility to hematological neoplasias of lymphoid origin.
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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Analysis of the distribution of genetic polymorphisms of biotransformation enzymes in cases and controls
DNA preparations from cases and controls were subjected to genotype analysis of CYP1A1 (3'-flanking region), CYP2E1 (5'-flanking region and intron 6), EPHX (exons 3 and 4), GSTM1 (deletion), GSTP1 (exon 5) and GSTT1 (deletion). The data obtained are summarized in Table 1. The observed frequencies and genotype distributions in our control group did not differ significantly from data on the majority of other European Caucasian subpopulations (36). The distribution of CYP2E1-intron 6 genotypes was significantly different between cases and controls (Table 2). When patients with lymphomas were divided into subgroups according to histological type of tumor, we found that the distribution of genotypes of CYP2E1-intron 6 was significantly different between the control and NHL groups, especially the group with aggressive diffuse NHL. However, it must be noted that when variant C/C and C/D genotypes in CYP2E1-intron 6 in the control and NHL groups were combined, statistical analysis failed to prove that this effect was significant. Calculations of relative risk [odds ratio (OR)] suggested that carriers of heterozygous genotype C/D are not at risk, as well as the group composed of combined holders of C/D and C/C genotypes (Table 3). The significant differences observed in distributions of genotypes (Table 2) were most probably caused by disproportion of homozygous mutant genotype C/C (no holders among controls, two holders among lymphomas, NHL, and one holder among diffuse NHL). Thus, the role of CYP2E1-intron 6 polymorphism as a risk factor in lymphoproliferative disorders remains questionable.
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Other data indicate a significant difference in the distribution of genotypes of EPHX-exon 3 between male controls and patients with lymphomas, especially of NHL (Table 2). Calculations of OR have shown that especially heterozygous genotype Tyr/His might be associated with the higher risk of lymphoma and NHL (Table 3). Male holders of mutant genotype His/His were also under lower risk of lymphoma and NHL but the relationship was not significant (Table 3). The difference in distribution of genotypes of EPHX-exon 3 between all patients and controls was not significant (P = 0.128) and neither was the difference between patients with NHL and controls (P = 0.13). On the contrary, the distribution of genotypes of GSTP1-exon 5 in the group of patients with MH was found to be significantly different from that in the control group (Table 2) and interestingly, this difference was even more pronounced in female patients. Calculations of OR have shown that the mutant homozygous Val/Val genotype of GSTP1-exon 5 was prevalent in all MH patients and female MH patients (Table 3), suggesting the possible negative role of the Val allele in the etiology of MH. The difference in distribution of genotypes of GSTP1-exon 5 between all patients and controls was not significant (P = 0.092) as well as the difference between patients with NHL and controls (P = 0.237), although the difference between male NHL and controls was at the borderline of significance (P = 0.059).
We did not find any association of genotypes of CYP1A1-3'-flanking region, CYP2E1-5'-flanking region, GSTM1null and GSTT1null with lymphomas. Our data support the results of Lemos et al. (37) who did not find any association of GSTM1null with incidence of MH (n = 25) and NHL (n = 71). Lemos et al. (37) also did not find association of polymorphisms of CYP2D6 and NAT2 with MH and NHL. Moreover, the lack of association of GSTT1null with lymphomas found in our study agrees with the data of Krajinovic et al. (38) who studied another lymphoproliferative disorder and did not find association of GSTT1null with childhood acute lymphoblastoid leukemia in a group of 177 patients. On the contrary, we did not confirm their observation on the prevalent incidence of CYP1A1m2 and GSTM1null genotypes in this group of patients with neoplasias of lymphoid origin [OR = 1.8, 95% confidence interval (CI) = 1.1–3.1; OR = 1.8, 95% CI = 1.2–2.6, respectively] (38).
The data on distribution of genotypes of CYP2E1, EPHX and GSTP1 in patients with lymphomas are not published so far. Recently, a higher incidence of the rare His allele in exon 3 of EPHX was observed in patients with colorectal cancer (OR = 3.8, 95% CI = 1.8–8.0) (39). Our results suggest the opposite relation, i.e. that males with the mutant EPHX-His allele in exon 3 are at lower risk of development of lymphomas and especially of NHL (Table 3). However, the study of Harrison et al. (39) did not discriminate between genders and moreover, the frequency of genotype His/His (EPHX-exon 3) found in their control group was quite low in comparison with data on our controls (Table 2). The observed discrepancy may also be explained by possible differences in the etiology of the two cancers. On the contrary, data of other authors comply with our results in that the Tyr allele of EPHX-exon 3 was found as a risk factor in ovarian cancer (OR = 2.6, 95% CI = 1.3–5.0) (40), lung cancer (OR = 2.66, 95% CI = 1.33–5.33) (41), pharynx, and larynx cancer (42). Although EPHX is usually considered a detoxification enzyme, it has been implicated in the metabolic activation of PAHs, e.g. 7,12-dimethylbenz[a]anthracene (DMBA) (43). This is very well supported by the fact that EPHX-null mice were found to be highly resistant to DMBA-induced carcinogenesis and totally resistant to tumorogenesis (44), and that subjects with slow EPHX alleles had a lower frequency of benzo[a]pyrenediolepoxide-serine albumin adducts and no DNA adducts in comparison with those possessing the fast alleles (45).
GSTP1 is overexpressed in some tumors and drug resistant cell lines, implying its possible role in resistance to anticancer drugs (27). In the study of Ryberg et al. (32), the frequency of Val/Val genotype in exon 5 of GSTP1 was significantly higher in lung cancer patients compared with healthy control individuals. Our data suggest that all patients, and especially females, with this genotype are under significantly higher risk of developing MH (Tables 2 and 3) (OR = 2.08, 95% CI = 1.05–4.14 for all MH; OR = 2.97, 95% CI = 1.16–7.61 for female MH). Data of many other authors suggest a possible role of the Val allele of GSTP1-exon 5 in oral cancer (46), renal cancer (OR = 2.4, 95% CI = 1.0–5.4) (47), and breast cancer (OR = 1.97, 95% CI = 0.77–5.02) (48).
When analyzing the number of heterozygotes for CYP1A1-5'-flank, CYP2E1-intron 6 and 3'-flank, and EPHX-exon 3 and 4 polymorphisms, we have noticed an unexpectedly low number of heterozygotes in the group of patients with lymphomas in comparison with controls. Lymphoproliferative disorders are known to be characterized by chromosomal instability and thus it seems possible that this apparent decrease is due to the loss of heterozygozity in DNA of lymphocytes used for genotype assessment. Similar findings were already reported by Lemos et al. (37) and further studies will be needed to clarify this point.
We have found gender-related differences in the distribution of genotypes of EPHX-exon 3 and GSTP1-exon 5 in patients with lymphomas. Such differences in MH or NHL were not reported, although Krajinovic et al. (38) found gender-related differences in the distribution of CYP1A1m4 genotype in patients with acute lymphoblastic leukemia. It is highly probable that the source and extent of exposure to xenobiotics differs between both genders as well as levels of certain steroids which have been shown to regulate transcription of biotransformation enzymes (e.g. androgens, estrogens, growth hormone etc). The fact that EPHX-exon 3 allele His is under-represented in males with NHL suggested a possible gender-specific protective role for this allele and may partly explain the higher prevalence of NHL in males (ratio males:females in our sample set was 
1:1.4). However, we cannot exclude the possibility that the existence of linkage disequilibrium of the EPHX locus with other adjacent gene(s) involved in carcinogenesis could be responsible for the effect observed.
Analysis of the influence of the distribution of genetic polymorphisms of biotransformation enzymes on the clinico-pathological characteristics of the disease
The results reported above, suggesting a possible association of genotypes of biotransformation enzymes with incidence of lymphomas, were confirmed by more detailed analysis of clinico-pathological characteristics of lymphomas. Grading of NHL seemed to be affected by genotypes of CYP2E1-intron 6. The holders of a normal D allele of CYP2E1 in intron 6 were significantly over-represented in the group of patients with medium and high grade NHL in comparison with the low grade group (OR = 0.17, 95% CI = 0.04–0.71) (Table 4). The meaning of this result remains unknown as there are no similar reports on the role of CYP2E1-intron 6 polymorphism in the progression of lymphoproliferative cancer disease in the literature.
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The distribution of polymorphisms in exon 5 of GSTP1 seemed to be significantly different between groups of patients with various sizes of NHL tumors (Table 4). Patients with tumors <5 cm had the Ile/Val (OR = 0.24, 95% CI = 0.09–0.65) or Val/Val genotypes (OR = 0.47, 95% CI = 0.13–1.71) more frequently than those with larger tumors (Table 4). This trend was particularly evident in comparison with the control group. A similar trend was reported by Nedelcheva-Kristensen et al. (49) who found over-representation of the variant Val allele in patients with breast cancer who had tumors <2 cm compared with the group of patients with tumors >2 cm. These authors also found an association of the GSTP1-exon 5 Val allele with an increased frequency of loss of heterozygozity and mutations in the p53 locus (49). Thus, it seems that the variant of GSTP1 with Val in codon 105 or another possibly linked alteration of this or adjacent genes may contribute to the accumulation of genetic damage during tumor progression. On the contrary, although not significant (P = 0.099), the Val/Val genotype of GSTP1-exon 5 showed a 3-fold decrease in risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia (50).
No significant association was found between all the studied genotypes and clinical stage, performance status, presence of symptoms, extranodal involvement or result of therapy.
By analysis of all the factors followed up, we have found that the average age of patients in the MH group was significantly lower than that in the group of NHL patients (32.1 ± 12.3 versus 54.4 ± 16.8, mean ± SD in years; F = 1.87, P < 0.001). There were also significant differences in the presence of symptoms (fever, night sweats, weight loss >10% in 6 months) and in the result of chemotherapy between MH and NHL patients (
2 = 5.51, d.f. = 1 with Yates correction, P = 0.019). Our results are in good agreement with previously published data (51).
Taken together, our findings seem to suggest an influence of genetic polymorphisms of xenobiotic-metabolizing enzymes, particularly CYP2E1-intron 6, EPHX-exon 3 and GSTP1-exon 5, on the susceptibility to lymphoproliferative disorders, possibly by change of the ratio of activation/detoxification of procarcinogens or by linkage to another cancer-causative gene. Some of the associations observed in this study involved grading and tumor size. Further research of these interactions, including analysis of larger numbers of samples, may allow a more precise identification of risk factors and can contribute towards understanding the molecular mechanisms underlying the development and progression of lymphomas.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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Materials
Phenol, chloroform, RNase A, proteinase K, RedTaq polymerase and chemicals for preparation of buffers were purchased from Sigma Chemical. Restriction enzymes and deoxynucleotides (dATP, dCTP, dGTP and dTTP) were products of New England Biolabs. PCR was performed using a GeneAmp 2400 thermocycler (Perkin Elmer). UltraPure agarose was supplied by Life Technologies. Oligonucleotide primers were synthesized by Generi Biotech.
Subjects
Blood samples were obtained from 76 MH (44 females and 32 males) and 143 NHL (66 females and 77 males) cases. The recruited patients comprised of white Caucasians attended at the 1st Department of Internal Medicine of the University Hospital in Praha 2. The following data on patients were retrieved from medical records: age, sex, clinical stage, presence of symptoms, nodal status, tumor size and grade, histopathological classification of tumor, performance status, international prognostic factor, chemotherapy and result of chemotherapy. A control group was composed of 455 unrelated subjects of Caucasian origin. Controls were recruited mainly from staff of the National Institute of Public Health, 3rd Medical Faculty and inhabitants of houses for elderly citizens living in the same urban area as patients. Controls had no previous medical record of lymphoma or other malignancies. The composition of the control group was comparable to cases in terms of age and sex (247 females and 208 males, prevalence of subjects older than 50). Patients and controls were asked to read and sign an informed consent in agreement with requirements of the Ethical Commission of the National Institute of Public Health in Praha.
DNA extraction
Genomic DNA was isolated from peripheral lymphocytes by the phenol/chloroform extraction method described by Sugimura et al. (52).
Genotyping
Genotypes of biotransformation enzymes were assayed with PCR–restriction fragment length polymorphism-based methods. For conditions of PCR reactions see Table 5. Briefly, DNA (50 ng) was amplified in total volume of 25 µl of PCR buffer (50 mM KCl, 10 mM Tris–HCl pH 8.3), 0.2 mM dNTP mix, 0.25 mM forward and reverse primer, 1.5 mM MgCl2 and 1U of RedTaq polymerase. Conditions for PCR cycling were in general: initial denaturation at 94°C for 5 min followed by 35 cycles of 94°C for 30 s, 30 s of annealing (for temperatures see Table 5) and elongation at 72°C for 60 s. For analysis of genotypes in GSTM1, GSTP1 and GSTT1, the multiplex method described by Nedelcheva-Kristensen et al. (50) was used. The resulting PCR fragments were subjected to restriction cleavage by corresponding restriction enzymes (Table 5). Horizontal agarose gel electrophoresis and staining with ethidium bromide were used for visualization and assessment of the results.
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Statistical analysis
Frequencies of particular genotypes were calculated as q = (2a + b)/n, where a = number of homozygotes, b = number of heterozygotes and n = number of analyzed alleles. We have tested associations between prevalence of particular genotypes and the occurrence of all lymphomas (versus controls), MH, NHL and subtypes of NHL (follicular NHL or diffuse NHL). We have also analyzed the influence of sex. Thus, in this subset of statistical analyses about 120 tests were performed. Subsequently, testing of prevalence of combinations of genotypes (CYPs + GSTs and EPHX + GSTs) and the occurrence of lymphomas (versus controls), MH, and NHL was also performed (45 tests). In order to investigate associations between particular genotypes and clinicopathological characteristics of the disease, we have analyzed the following subgroups of NHL patients: low grade versus medium grade plus high grade; extranodal involvement, yes versus no; tumor size
5 cm versus >5 cm; clinical stage, I versus II versus III versus IV; presence of symptoms, yes versus no; relapse in the last 3 years, yes versus no (56 tests). Due to rareness of the CYP1A1-m2/m2, CYP2E1-c2/c2 and CYP2E1-C/C genotypes, most statistical analyses were performed by combining heterozygotes and homozygote mutant allele holders. Associations were quantified by calculating OR with profile likelihood-based 95% CI (Win SPSS v8.0 program, SPSS). The statistical significance of the differences in distribution of genotypes between cases and controls or between particular patient groups was analyzed using contingency tables by computer program StatGraphics v7.0 (Manugistics). When the group size was less than 40 or when expected values in contingency tables were less than five, Fisher’s exact test was used. The P value <0.05 was considered as significant. |
ACKNOWLEDGEMENTS |
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The authors would like to express their sincere thanks to Ing. Zdenek Roth and Dr Zdenek Smerhovsky (National Institute of Public Health) for help with statistical analyses. The work at this project was supported by grant no. 6747-3 from the Internal Grant Agency of The Czech Ministry of Health.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +420 2 6708 2711; Fax: +420 2 6731 1236; Email: psoucek@szu.cz
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REFERENCES |
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