Polymorphism in cytochrome P450 CYP2D6, CYP1A1, CYP2E1 and glutathione S-transferase, GSTM1, GSTM3, GSTT1 and susceptibility to tobacco-related cancers

studies in upper aerodigestive tract cancers

C. Matthias, U. Bockmühl, V. Jahnke, P. W. Jones, J. D. Hayes, J. Alldersea, J. Gilford, L. Bailey, J. Bath, S. F. Worrall, P. Hand, A. A. Fryer, R. C. Strange

    Research output: Contribution to journalArticle

    147 Citations (Scopus)

    Abstract

    Glutathione S-transferase GSTM1, GSTM3 and GSTT1 and cytochrome P450 CYP2D6, CYP1A1 and CYP2E1 loci are susceptibility candidates for cancers of the upper aerodigestive tract because putatively protective and risk genotypes have been identified from studies in other diseases associated with alcohol and tobacco consumption. We describe genotype frequencies in 398 oral, pharyngeal and laryngeal squamous cell carcinoma patients and 219 control individuals. Of the genotypes presumed to be protective, only GSTM1 A/B influenced susceptibility; the GSTM1 A/B frequency was lower in the patients than the control individuals both before [odds ratio = 0.3, 95% confidence interval (CI) 0.1-0.7] and after correction for imbalances in age, sex, smoking and alcohol consumption (odds ratio = 0.2, 95% CI 0.1-0.5). Of the putatively risk genotypes, GSTM3 AA, previously associated with susceptibility to skin cancer, was higher in the cases (odds ratio = 1.6, 95% CI 1.1-2.4). Dividing cases into oral/pharyngeal and laryngeal squamous cell carcinoma showed the GSTM3 AA frequency was higher in laryngeal squamous cell carcinoma than control individuals (odds ratio = 1.6, 95% CI 1.1-2.5) and the difference between control individuals and oral/pharyngeal squamous cell carcinoma approached significance (odds ratio = 1.7, 95% CI 1.0-2.8). The putatively protective GSTM3 BB genotype was lower in patients with glottic (1.0%) than supraglottic (3.0%) squamous cell carcinoma. We identified no differences between patients and control individuals in the frequencies of presumed risk genotypes (e.g. CYP2D6 EM, CYP1A1 m1/m1, CYP1A1 Ile/Ile, CYP2E1 DD, CYP2E1 c1c1, GSTT1 null) or, interactions between genotypes and smoking or alcohol consumption. We conclude, first, that mu class glutathione S-transferase influence risk of upper aerodigestive tract cancers thereby complementing studies in skin cancer patients showing GSTM1 A/B is protective, while GSTM3 AA moderately increases risk. The influence of GSTM1 A/B, but not GSTM1 A or GSTM1 B (mostly heterozygotes with GSTM1*0) suggests that two expressed alleles may attenuate risk. While we found immunohistochemical evidence of GSTM3 expression in the cilia lining the larynx, the biochemical consequences of the polymorphism are unclear. Indeed, the influence of the gene may reflect linkage disequilibrium with another gene. However, we did not find an association with GSTM1 genotypes. Second, we conclude that the CYP2D6, CYP2E1, CYP1A1 and GSTT1 alleles studied, although putatively good candidates, either do not determine the effectiveness of detoxification of tobacco-derived carcinogens in the upper aerodigestive tract or, that chronic consumption of tobacco and alcohol overwhelms enzyme defences, irrespective of genotype.

    Original languageEnglish
    Pages (from-to)91-100
    Number of pages10
    JournalPharmacogenetics
    Volume8
    Issue number2
    Publication statusPublished - Apr 1998

    Fingerprint

    Cytochrome P-450 CYP2E1
    Cytochrome P-450 CYP2D6
    Cytochrome P-450 CYP1A1
    Glutathione Transferase
    Cytochrome P-450 Enzyme System
    Tobacco
    Genotype
    Squamous Cell Carcinoma
    Alcohol Drinking
    Neoplasms
    Odds Ratio
    Confidence Intervals
    Tobacco Use
    Skin Neoplasms
    Smoking
    Alleles
    Cilia
    Linkage Disequilibrium
    Heterozygote
    Larynx

    Keywords

    • Aged
    • Base Sequence
    • Carcinoma, Squamous Cell/genetics
    • Cytochrome P-450 Enzyme System/genetics
    • DNA Primers
    • Female
    • Genetic Predisposition to Disease
    • Genotype
    • Glutathione Transferase/genetics
    • Humans
    • Immunohistochemistry
    • Isoenzymes/genetics
    • Laryngeal Neoplasms/genetics
    • Male
    • Middle Aged
    • Mouth Neoplasms/genetics
    • Pharyngeal Neoplasms/genetics
    • Polymorphism, Genetic
    • Smoking/adverse effects

    Cite this

    Matthias, C. ; Bockmühl, U. ; Jahnke, V. ; Jones, P. W. ; Hayes, J. D. ; Alldersea, J. ; Gilford, J. ; Bailey, L. ; Bath, J. ; Worrall, S. F. ; Hand, P. ; Fryer, A. A. ; Strange, R. C. / Polymorphism in cytochrome P450 CYP2D6, CYP1A1, CYP2E1 and glutathione S-transferase, GSTM1, GSTM3, GSTT1 and susceptibility to tobacco-related cancers : studies in upper aerodigestive tract cancers. In: Pharmacogenetics. 1998 ; Vol. 8, No. 2. pp. 91-100.
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    abstract = "Glutathione S-transferase GSTM1, GSTM3 and GSTT1 and cytochrome P450 CYP2D6, CYP1A1 and CYP2E1 loci are susceptibility candidates for cancers of the upper aerodigestive tract because putatively protective and risk genotypes have been identified from studies in other diseases associated with alcohol and tobacco consumption. We describe genotype frequencies in 398 oral, pharyngeal and laryngeal squamous cell carcinoma patients and 219 control individuals. Of the genotypes presumed to be protective, only GSTM1 A/B influenced susceptibility; the GSTM1 A/B frequency was lower in the patients than the control individuals both before [odds ratio = 0.3, 95{\%} confidence interval (CI) 0.1-0.7] and after correction for imbalances in age, sex, smoking and alcohol consumption (odds ratio = 0.2, 95{\%} CI 0.1-0.5). Of the putatively risk genotypes, GSTM3 AA, previously associated with susceptibility to skin cancer, was higher in the cases (odds ratio = 1.6, 95{\%} CI 1.1-2.4). Dividing cases into oral/pharyngeal and laryngeal squamous cell carcinoma showed the GSTM3 AA frequency was higher in laryngeal squamous cell carcinoma than control individuals (odds ratio = 1.6, 95{\%} CI 1.1-2.5) and the difference between control individuals and oral/pharyngeal squamous cell carcinoma approached significance (odds ratio = 1.7, 95{\%} CI 1.0-2.8). The putatively protective GSTM3 BB genotype was lower in patients with glottic (1.0{\%}) than supraglottic (3.0{\%}) squamous cell carcinoma. We identified no differences between patients and control individuals in the frequencies of presumed risk genotypes (e.g. CYP2D6 EM, CYP1A1 m1/m1, CYP1A1 Ile/Ile, CYP2E1 DD, CYP2E1 c1c1, GSTT1 null) or, interactions between genotypes and smoking or alcohol consumption. We conclude, first, that mu class glutathione S-transferase influence risk of upper aerodigestive tract cancers thereby complementing studies in skin cancer patients showing GSTM1 A/B is protective, while GSTM3 AA moderately increases risk. The influence of GSTM1 A/B, but not GSTM1 A or GSTM1 B (mostly heterozygotes with GSTM1*0) suggests that two expressed alleles may attenuate risk. While we found immunohistochemical evidence of GSTM3 expression in the cilia lining the larynx, the biochemical consequences of the polymorphism are unclear. Indeed, the influence of the gene may reflect linkage disequilibrium with another gene. However, we did not find an association with GSTM1 genotypes. Second, we conclude that the CYP2D6, CYP2E1, CYP1A1 and GSTT1 alleles studied, although putatively good candidates, either do not determine the effectiveness of detoxification of tobacco-derived carcinogens in the upper aerodigestive tract or, that chronic consumption of tobacco and alcohol overwhelms enzyme defences, irrespective of genotype.",
    keywords = "Aged, Base Sequence, Carcinoma, Squamous Cell/genetics, Cytochrome P-450 Enzyme System/genetics, DNA Primers, Female, Genetic Predisposition to Disease, Genotype, Glutathione Transferase/genetics, Humans, Immunohistochemistry, Isoenzymes/genetics, Laryngeal Neoplasms/genetics, Male, Middle Aged, Mouth Neoplasms/genetics, Pharyngeal Neoplasms/genetics, Polymorphism, Genetic, Smoking/adverse effects",
    author = "C. Matthias and U. Bockm{\"u}hl and V. Jahnke and Jones, {P. W.} and Hayes, {J. D.} and J. Alldersea and J. Gilford and L. Bailey and J. Bath and Worrall, {S. F.} and P. Hand and Fryer, {A. A.} and Strange, {R. C.}",
    year = "1998",
    month = "4",
    language = "English",
    volume = "8",
    pages = "91--100",
    journal = "Pharmacogenetics",
    issn = "0960-314X",
    publisher = "Lippincott Williams and Wilkins",
    number = "2",

    }

    Matthias, C, Bockmühl, U, Jahnke, V, Jones, PW, Hayes, JD, Alldersea, J, Gilford, J, Bailey, L, Bath, J, Worrall, SF, Hand, P, Fryer, AA & Strange, RC 1998, 'Polymorphism in cytochrome P450 CYP2D6, CYP1A1, CYP2E1 and glutathione S-transferase, GSTM1, GSTM3, GSTT1 and susceptibility to tobacco-related cancers: studies in upper aerodigestive tract cancers', Pharmacogenetics, vol. 8, no. 2, pp. 91-100.

    Polymorphism in cytochrome P450 CYP2D6, CYP1A1, CYP2E1 and glutathione S-transferase, GSTM1, GSTM3, GSTT1 and susceptibility to tobacco-related cancers : studies in upper aerodigestive tract cancers. / Matthias, C.; Bockmühl, U.; Jahnke, V.; Jones, P. W.; Hayes, J. D.; Alldersea, J.; Gilford, J.; Bailey, L.; Bath, J.; Worrall, S. F.; Hand, P.; Fryer, A. A.; Strange, R. C.

    In: Pharmacogenetics, Vol. 8, No. 2, 04.1998, p. 91-100.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Polymorphism in cytochrome P450 CYP2D6, CYP1A1, CYP2E1 and glutathione S-transferase, GSTM1, GSTM3, GSTT1 and susceptibility to tobacco-related cancers

    T2 - studies in upper aerodigestive tract cancers

    AU - Matthias, C.

    AU - Bockmühl, U.

    AU - Jahnke, V.

    AU - Jones, P. W.

    AU - Hayes, J. D.

    AU - Alldersea, J.

    AU - Gilford, J.

    AU - Bailey, L.

    AU - Bath, J.

    AU - Worrall, S. F.

    AU - Hand, P.

    AU - Fryer, A. A.

    AU - Strange, R. C.

    PY - 1998/4

    Y1 - 1998/4

    N2 - Glutathione S-transferase GSTM1, GSTM3 and GSTT1 and cytochrome P450 CYP2D6, CYP1A1 and CYP2E1 loci are susceptibility candidates for cancers of the upper aerodigestive tract because putatively protective and risk genotypes have been identified from studies in other diseases associated with alcohol and tobacco consumption. We describe genotype frequencies in 398 oral, pharyngeal and laryngeal squamous cell carcinoma patients and 219 control individuals. Of the genotypes presumed to be protective, only GSTM1 A/B influenced susceptibility; the GSTM1 A/B frequency was lower in the patients than the control individuals both before [odds ratio = 0.3, 95% confidence interval (CI) 0.1-0.7] and after correction for imbalances in age, sex, smoking and alcohol consumption (odds ratio = 0.2, 95% CI 0.1-0.5). Of the putatively risk genotypes, GSTM3 AA, previously associated with susceptibility to skin cancer, was higher in the cases (odds ratio = 1.6, 95% CI 1.1-2.4). Dividing cases into oral/pharyngeal and laryngeal squamous cell carcinoma showed the GSTM3 AA frequency was higher in laryngeal squamous cell carcinoma than control individuals (odds ratio = 1.6, 95% CI 1.1-2.5) and the difference between control individuals and oral/pharyngeal squamous cell carcinoma approached significance (odds ratio = 1.7, 95% CI 1.0-2.8). The putatively protective GSTM3 BB genotype was lower in patients with glottic (1.0%) than supraglottic (3.0%) squamous cell carcinoma. We identified no differences between patients and control individuals in the frequencies of presumed risk genotypes (e.g. CYP2D6 EM, CYP1A1 m1/m1, CYP1A1 Ile/Ile, CYP2E1 DD, CYP2E1 c1c1, GSTT1 null) or, interactions between genotypes and smoking or alcohol consumption. We conclude, first, that mu class glutathione S-transferase influence risk of upper aerodigestive tract cancers thereby complementing studies in skin cancer patients showing GSTM1 A/B is protective, while GSTM3 AA moderately increases risk. The influence of GSTM1 A/B, but not GSTM1 A or GSTM1 B (mostly heterozygotes with GSTM1*0) suggests that two expressed alleles may attenuate risk. While we found immunohistochemical evidence of GSTM3 expression in the cilia lining the larynx, the biochemical consequences of the polymorphism are unclear. Indeed, the influence of the gene may reflect linkage disequilibrium with another gene. However, we did not find an association with GSTM1 genotypes. Second, we conclude that the CYP2D6, CYP2E1, CYP1A1 and GSTT1 alleles studied, although putatively good candidates, either do not determine the effectiveness of detoxification of tobacco-derived carcinogens in the upper aerodigestive tract or, that chronic consumption of tobacco and alcohol overwhelms enzyme defences, irrespective of genotype.

    AB - Glutathione S-transferase GSTM1, GSTM3 and GSTT1 and cytochrome P450 CYP2D6, CYP1A1 and CYP2E1 loci are susceptibility candidates for cancers of the upper aerodigestive tract because putatively protective and risk genotypes have been identified from studies in other diseases associated with alcohol and tobacco consumption. We describe genotype frequencies in 398 oral, pharyngeal and laryngeal squamous cell carcinoma patients and 219 control individuals. Of the genotypes presumed to be protective, only GSTM1 A/B influenced susceptibility; the GSTM1 A/B frequency was lower in the patients than the control individuals both before [odds ratio = 0.3, 95% confidence interval (CI) 0.1-0.7] and after correction for imbalances in age, sex, smoking and alcohol consumption (odds ratio = 0.2, 95% CI 0.1-0.5). Of the putatively risk genotypes, GSTM3 AA, previously associated with susceptibility to skin cancer, was higher in the cases (odds ratio = 1.6, 95% CI 1.1-2.4). Dividing cases into oral/pharyngeal and laryngeal squamous cell carcinoma showed the GSTM3 AA frequency was higher in laryngeal squamous cell carcinoma than control individuals (odds ratio = 1.6, 95% CI 1.1-2.5) and the difference between control individuals and oral/pharyngeal squamous cell carcinoma approached significance (odds ratio = 1.7, 95% CI 1.0-2.8). The putatively protective GSTM3 BB genotype was lower in patients with glottic (1.0%) than supraglottic (3.0%) squamous cell carcinoma. We identified no differences between patients and control individuals in the frequencies of presumed risk genotypes (e.g. CYP2D6 EM, CYP1A1 m1/m1, CYP1A1 Ile/Ile, CYP2E1 DD, CYP2E1 c1c1, GSTT1 null) or, interactions between genotypes and smoking or alcohol consumption. We conclude, first, that mu class glutathione S-transferase influence risk of upper aerodigestive tract cancers thereby complementing studies in skin cancer patients showing GSTM1 A/B is protective, while GSTM3 AA moderately increases risk. The influence of GSTM1 A/B, but not GSTM1 A or GSTM1 B (mostly heterozygotes with GSTM1*0) suggests that two expressed alleles may attenuate risk. While we found immunohistochemical evidence of GSTM3 expression in the cilia lining the larynx, the biochemical consequences of the polymorphism are unclear. Indeed, the influence of the gene may reflect linkage disequilibrium with another gene. However, we did not find an association with GSTM1 genotypes. Second, we conclude that the CYP2D6, CYP2E1, CYP1A1 and GSTT1 alleles studied, although putatively good candidates, either do not determine the effectiveness of detoxification of tobacco-derived carcinogens in the upper aerodigestive tract or, that chronic consumption of tobacco and alcohol overwhelms enzyme defences, irrespective of genotype.

    KW - Aged

    KW - Base Sequence

    KW - Carcinoma, Squamous Cell/genetics

    KW - Cytochrome P-450 Enzyme System/genetics

    KW - DNA Primers

    KW - Female

    KW - Genetic Predisposition to Disease

    KW - Genotype

    KW - Glutathione Transferase/genetics

    KW - Humans

    KW - Immunohistochemistry

    KW - Isoenzymes/genetics

    KW - Laryngeal Neoplasms/genetics

    KW - Male

    KW - Middle Aged

    KW - Mouth Neoplasms/genetics

    KW - Pharyngeal Neoplasms/genetics

    KW - Polymorphism, Genetic

    KW - Smoking/adverse effects

    M3 - Article

    VL - 8

    SP - 91

    EP - 100

    JO - Pharmacogenetics

    JF - Pharmacogenetics

    SN - 0960-314X

    IS - 2

    ER -