Accepted manuscript
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
Molecular carcinogenesis, Vol.52(10), pp.791-799
10/2013
Handle:
https://hdl.handle.net/2376/107202
PMCID: PMC3595361
PMID: 22610501
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’-untraslated 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 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 glutathione 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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Details
- 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
- Creators
- Sailendra N Nichenametla - Department of Public Health Sciences, Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA 17033Joshua E Muscat - Department of Public Health Sciences, Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA 17033Jason G Liao - Department of Public Health Sciences, Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA 17033Philip Lazarus - Department of Public Health Sciences, Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA 17033John P Richie - Department of Public Health Sciences, Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA 17033
- Publication Details
- Molecular carcinogenesis, Vol.52(10), pp.791-799
- Academic Unit
- Department of Pharmaceutical Sciences
- Publisher
- Wiley
- Number of pages
- 9
- Grant note
- P01 CA068384 || CA / National Cancer Institute : NCI R01 DE013158 || DE / National Institute of Dental and Craniofacial Research : NIDCR
- Identifiers
- 99900546515101842
- Language
- English
- Resource Type
- Accepted manuscript