hOGG1 polymorphism and loss of heterozygosity (LOH): significance for lung cancer susceptibility in a caucasian population.
Oxidative damage is implicated in several chronic diseases including cancer. 8-Hydroxyguanine (8-oxoG) is one of the major promutagenic DNA lesions, which is produced by reactive oxygen species, causes G:C to T:A transversions and is excised by OGG1, an 8-oxoG specific DNA glycosylase/AP-Lyase. In a nested case-control study, gDNA from 105 Caucasian primary non-small cell lung cancer cases and 105 matched controls was screened for 6 possible new polymorphic sites in the human OGG1 gene, detected previously mainly in tumour tissue. The previously described Ser(326)Cys polymorphism was found to be common (allele frequency 0.22) in Caucasians. However, no major difference in Ser(326)Cys genotype distribution could be detected between cases and controls. Two 5;-end polymorphisms previously found in Japanese as well as Arg(131)Gln could not be detected in this population. An Ala(85)Ser polymorphism was found in 2 controls, whereas Arg(46)Gln was detected in only 1 case. As the hOGG1 gene is mapped (3p26.2) to a region frequently lost in primary lung tumours, the frequency of loss of heterozygosity (LOH) was investigated. Forty-three percent of the studied lung tumours exhibited loss of one of the hOGG1 alleles. The wt Ser(326) allele was not predominantly lost in our sample set, which suggests a minor role of this polymorphism in tumourgenesis. Our results show that LOH at the hOGG1 gene locus is a very common occurrence in lung tumourgenesis, possibly leading to increased mutational damage due to ROS in smokers. However, the hOGG1 polymorphisms studied are probably not major contributors to individual lung cancer susceptibility in Caucasians.
Wikman
H
H
German Cancer Research Center (DKFZ), Division of Toxicology and Cancer Risk Factors, Heidelberg, Germany.
Risch
A
A
Klimek
F
F
Schmezer
P
P
Spiegelhalder
B
B
Dienemann
H
H
Kayser
K
K
Schulz
V
V
Drings
P
P
Bartsch
H
H
D000230:Adenocarcinoma / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D016022:Case-Control Studies; D043382:DNA-Formamidopyrimidine Glycosylase; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009699:N-Glycosyl Hydrolases / Q000235:genetics*; D021141:Nucleic Acid Amplification Techniques; D010865:Pilot Projects; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D044465:White People
D043382:DNA-Formamidopyrimidine Glycosylase; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007527:Isoenzymes; D009699:N-Glycosyl Hydrolases; C496556:GSTP1 protein, human