Association between lung cancer risk and single nucleotide polymorphisms in the first intron and codon 178 of the DNA repair gene, O6-alkylguanine-DNA alkyltransferase.
The association between lung cancer risk and 2 polymorphisms, rs12268840 and rs2308327 (codon K178R), in the DNA repair protein, O(6)-alkylguanine-DNA alkyltransferase, which are associated with interindividual differences in activity, have been investigated in 3 hospital-based case-control studies. Genotyping was carried out on 617 subjects of whom 255 had lung cancer. In 2 of the 3 series, there was a significant inverse association between the 178R allele and case status (p < 0.05). In a meta-analysis, the odds ratio (95% CI) associated with the 178R allele relative to the 178K allele was 0.64 (0.45-0.92, p = 0.01) and 0.51 (0.24-1.11, p = 0.09) in fixed effects and random effects models, respectively. In a pooled analysis, after adjustment for sex, age, pack years and series, the OR (95% CI) for a heterozygote was 0.67 (0.45-1.01) and for a 178R homozygote was 0.10 (0.01-0.94); the trend for a decreased risk with the number of R alleles was significant (p = 0.008). This trend was particularly pronounced in heavy smokers (trend test p = 0.003), but not significant in light smokers (p = 0.73). There was no evidence of an association between rs12268840 and lung cancer risk. These results suggest that the R allele may protect against lung cancer, specifically in heavy smokers, an effect that may result from this polymorphism affecting the function of the MGMT protein and/or levels in MGMT activity.
Crosbie
Philip A J
PA
Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, United Kingdom.
McGown
Gail
G
Thorncroft
Mary R
MR
O'Donnell
Paul N S
PN
Barber
Philip V
PV
Lewis
Sarah J
SJ
Harrison
Kathryn L
KL
Agius
Raymond M
RM
Santibáñez-Koref
Mauro F
MF
Margison
Geoffrey P
GP
Povey
Andrew C
AC
D000230:Adenocarcinoma / Q000201:enzymology / Q000209:etiology; D000368:Aged; D018288:Carcinoma, Small Cell / Q000201:enzymology / Q000209:etiology*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000209:etiology; D016022:Case-Control Studies; D003062:Codon / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics*; D008175:Lung Neoplasms / Q000201:enzymology / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects
D003062:Codon; D019853:O(6)-Methylguanine-DNA Methyltransferase