The effect of hOGG1 and glutathione peroxidase I genotypes and 3p chromosomal loss on 8-hydroxydeoxyguanosine levels in lung cancer.
Polymorphic genes for the peroxide scavenger glutathione peroxidase I (GPX1) and 8-hydroxydeoxyguanosine (8-OHdG) DNA glycosylase/apurinic (AP) lyase (hOGG1) map to loci on chromosome 3p which are subject to frequent loss of heterozygosity (LOH) in lung tumours. Levels of the pro-mutagenic, oxidative DNA lesion 8-OHdG, were measured in 37 paired normal and tumorous lung specimens using HPLC with electrochemical detection. Lung tumours were also analysed for 3p LOH by fluorescent PCR with Genescan analysis. No significant difference was observed between 8-OHdG levels in tumour [7.7 +/- 6.7 (mean +/- SE) 8-OHdG/10(6) 2'-deoxyguanosine (dG)] and normal (8.1 +/- 8.8 8-OHdG/10(6) dG) lung tissue. Adduct levels in normal lung tissue DNA were not associated with constitutive hOGG1 genotype although there was a trend towards lower 8-OHdG levels in individuals possessing the ALA6 GPX1 polymorphism. Lung tumours exhibiting 3p LOH (40%) contained higher levels of 8-OHdG adducts (10.9 +/- 2.6 8-OHdG/10(6) dG) (P = 0.05) and lower GPX1 enzyme activity [45.5 nmol glutathione (GSH)/min/mg] (P = 0.09) when compared with tumours without LOH at these sites (5.55 +/- 0.87 8-OHdG/10(6) dG and 63.6 nmol GSH/min/mg, respectively). In conclusion, tumours with 3p LOH at loci associated with hOGG1 and GPX1 appear to have compromised oxidative defence mechanisms as measured by reduced GPX1 enzyme activity and elevated 8-OHdG levels and this may affect the prognosis of lung cancer patients.
Hardie
L J
LJ
Molecular Epidemiology Unit, School of Medicine, University of Leeds and Institute of Pathology, Algernon Firth Building, Leeds LS2 9JT, UK. medljh@leeds.ac.uk
Briggs
J A
JA
Davidson
L A
LA
Allan
J M
JM
King
R F
RF
Williams
G I
GI
Wild
C P
CP
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D019943:Amino Acid Substitution; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D018736:DNA Adducts; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D043382:DNA-Formamidopyrimidine Glycosylase; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000032:analysis; D005260:Female; D005838:Genotype; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000502:physiology; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D009699:N-Glycosyl Hydrolases / Q000235:genetics* / Q000502:physiology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D018384:Oxidative Stress; D011110:Polymorphism, Genetic; D012907:Smoking / Q000009:adverse effects
D018736:DNA Adducts; D004273:DNA, Neoplasm; D007527:Isoenzymes; D009363:Neoplasm Proteins; D000080242:8-Hydroxy-2'-Deoxyguanosine; D005979:Glutathione Peroxidase; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; D003849:Deoxyguanosine