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. Other Scholarly Work

Nichenametla, Sailendra N, Muscat, Joshua E, Liao, Jason G et al. (2013). 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. . 52(10), 791-799. 10.1002/mc.21923

cited authors

  • Nichenametla, Sailendra N; Muscat, Joshua E; Liao, Jason G; Lazarus, Philip; Richie, John P

fiu authors

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.

publication date

  • October 1, 2013

keywords

  • 5' Untranslated Regions
  • Adenocarcinoma
  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Large Cell
  • Carcinoma, Non-Small-Cell Lung
  • Carcinoma, Squamous Cell
  • Case-Control Studies
  • Digestive System Neoplasms
  • Female
  • Genotype
  • Glutamate-Cysteine Ligase
  • Humans
  • Lung
  • Lung Neoplasms
  • Male
  • Middle Aged
  • Polymerase Chain Reaction
  • Polymorphism, Genetic
  • Prognosis
  • Risk Factors
  • Small Cell Lung Carcinoma
  • Trinucleotide Repeats

Digital Object Identifier (DOI)

Medium

  • Print-Electronic

start page

  • 791

end page

  • 799

volume

  • 52

issue

  • 10