A functional trinucleotide repeat polymorphism in the 5′-untranslated region of the glutathione biosynthetic gene GCLC is associated with increased risk for lung and aerodigestive tract cancers

Sailendra N. Nichenametla, Joshua Muscat, Jiangang (Jason) Liao, Philip Lazarus, John Richie

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9 Citations (Scopus)

Abstract

Glutathione (GSH), the major intracellular antioxidant, protects against cancer development by detoxifying carcinogens and free radicals and strengthening the immune system. Recently, a GAG-trinucleotide repeat polymorphism in the 5′-untranslated region of the gene for the rate-limiting enzyme for GSH biosynthesis, γ-glutamine cysteine ligase (GCL), was shown to be associated with lowered GCL activity and GSH levels in vitro and in vivo. We tested the hypothesis that this functional polymorphism in GCL is associated with the risk for lung and aerodigestive tract cancers. To this end, we conducted a case-control study that included 375 lung cancer cases, 200 aerodigestive tract cancer cases, and 537 controls. GAG repeat genotype (4, 7, 8, 9, and 10 repeat alleles) was determined by capillary electrophoresis of PCR products from the repeat region of the GCL catalytic subunit (GCLC). Odds ratios (OR) were calculated by logistic regression and adjusted for risk factors, including age, sex, body mass index, and smoking history. The GAG-7/7 genotype was associated with a 1.9-fold increased risk of lung cancer and 2.6-fold increased risk of aerodigestive tract cancer compared to the wild-type GAG-9/9 (P<0.05). Similarly, the GAG-7 allele was associated with an increased risk of lung cancer (OR=1.5, P=0.01) and aerodigestive tract cancer (OR=2.3, P<0.001) compared to subjects without GAG-7 allele. These findings suggest that GSH synthesis affects the risk of lung and aerodigestive tract cancers, and further implicates a role for oxidative stress in the development of these cancers.

Original languageEnglish (US)
Pages (from-to)791-799
Number of pages9
JournalMolecular Carcinogenesis
Volume52
Issue number10
DOIs
StatePublished - Oct 1 2013

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Trinucleotide Repeats
5' Untranslated Regions
Glutathione
Catalytic Domain
Lung
Ligases
Glutamine
Cysteine
Genes
Neoplasms
Lung Neoplasms
Alleles
Odds Ratio
Genotype
Capillary Electrophoresis
Carcinogens
Free Radicals
Case-Control Studies
Immune System
Oxidative Stress

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

Cite this

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title = "A functional trinucleotide repeat polymorphism in the 5′-untranslated region of the glutathione biosynthetic gene GCLC is associated with increased risk for lung and aerodigestive tract cancers",
abstract = "Glutathione (GSH), the major intracellular antioxidant, protects against cancer development by detoxifying carcinogens and free radicals and strengthening the immune system. Recently, a GAG-trinucleotide repeat polymorphism in the 5′-untranslated region of the gene for the rate-limiting enzyme for GSH biosynthesis, γ-glutamine cysteine ligase (GCL), was shown to be associated with lowered GCL activity and GSH levels in vitro and in vivo. We tested the hypothesis that this functional polymorphism in GCL is associated with the risk for lung and aerodigestive tract cancers. To this end, we conducted a case-control study that included 375 lung cancer cases, 200 aerodigestive tract cancer cases, and 537 controls. GAG repeat genotype (4, 7, 8, 9, and 10 repeat alleles) was determined by capillary electrophoresis of PCR products from the repeat region of the GCL catalytic subunit (GCLC). Odds ratios (OR) were calculated by logistic regression and adjusted for risk factors, including age, sex, body mass index, and smoking history. The GAG-7/7 genotype was associated with a 1.9-fold increased risk of lung cancer and 2.6-fold increased risk of aerodigestive tract cancer compared to the wild-type GAG-9/9 (P<0.05). Similarly, the GAG-7 allele was associated with an increased risk of lung cancer (OR=1.5, P=0.01) and aerodigestive tract cancer (OR=2.3, P<0.001) compared to subjects without GAG-7 allele. These findings suggest that GSH synthesis affects the risk of lung and aerodigestive tract cancers, and further implicates a role for oxidative stress in the development of these cancers.",
author = "Nichenametla, {Sailendra N.} and Joshua Muscat and Liao, {Jiangang (Jason)} and Philip Lazarus and John Richie",
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T1 - A functional trinucleotide repeat polymorphism in the 5′-untranslated region of the glutathione biosynthetic gene GCLC is associated with increased risk for lung and aerodigestive tract cancers

AU - Nichenametla, Sailendra N.

AU - Muscat, Joshua

AU - Liao, Jiangang (Jason)

AU - Lazarus, Philip

AU - Richie, John

PY - 2013/10/1

Y1 - 2013/10/1

N2 - Glutathione (GSH), the major intracellular antioxidant, protects against cancer development by detoxifying carcinogens and free radicals and strengthening the immune system. Recently, a GAG-trinucleotide repeat polymorphism in the 5′-untranslated region of the gene for the rate-limiting enzyme for GSH biosynthesis, γ-glutamine cysteine ligase (GCL), was shown to be associated with lowered GCL activity and GSH levels in vitro and in vivo. We tested the hypothesis that this functional polymorphism in GCL is associated with the risk for lung and aerodigestive tract cancers. To this end, we conducted a case-control study that included 375 lung cancer cases, 200 aerodigestive tract cancer cases, and 537 controls. GAG repeat genotype (4, 7, 8, 9, and 10 repeat alleles) was determined by capillary electrophoresis of PCR products from the repeat region of the GCL catalytic subunit (GCLC). Odds ratios (OR) were calculated by logistic regression and adjusted for risk factors, including age, sex, body mass index, and smoking history. The GAG-7/7 genotype was associated with a 1.9-fold increased risk of lung cancer and 2.6-fold increased risk of aerodigestive tract cancer compared to the wild-type GAG-9/9 (P<0.05). Similarly, the GAG-7 allele was associated with an increased risk of lung cancer (OR=1.5, P=0.01) and aerodigestive tract cancer (OR=2.3, P<0.001) compared to subjects without GAG-7 allele. These findings suggest that GSH synthesis affects the risk of lung and aerodigestive tract cancers, and further implicates a role for oxidative stress in the development of these cancers.

AB - Glutathione (GSH), the major intracellular antioxidant, protects against cancer development by detoxifying carcinogens and free radicals and strengthening the immune system. Recently, a GAG-trinucleotide repeat polymorphism in the 5′-untranslated region of the gene for the rate-limiting enzyme for GSH biosynthesis, γ-glutamine cysteine ligase (GCL), was shown to be associated with lowered GCL activity and GSH levels in vitro and in vivo. We tested the hypothesis that this functional polymorphism in GCL is associated with the risk for lung and aerodigestive tract cancers. To this end, we conducted a case-control study that included 375 lung cancer cases, 200 aerodigestive tract cancer cases, and 537 controls. GAG repeat genotype (4, 7, 8, 9, and 10 repeat alleles) was determined by capillary electrophoresis of PCR products from the repeat region of the GCL catalytic subunit (GCLC). Odds ratios (OR) were calculated by logistic regression and adjusted for risk factors, including age, sex, body mass index, and smoking history. The GAG-7/7 genotype was associated with a 1.9-fold increased risk of lung cancer and 2.6-fold increased risk of aerodigestive tract cancer compared to the wild-type GAG-9/9 (P<0.05). Similarly, the GAG-7 allele was associated with an increased risk of lung cancer (OR=1.5, P=0.01) and aerodigestive tract cancer (OR=2.3, P<0.001) compared to subjects without GAG-7 allele. These findings suggest that GSH synthesis affects the risk of lung and aerodigestive tract cancers, and further implicates a role for oxidative stress in the development of these cancers.

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