Carcinogenesis Advance Access originally published online on November 21, 2006
Carcinogenesis 2007 28(5):988-994; doi:10.1093/carcin/bgl225
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172G>T variant in the 5' untranslated region of DNA repair gene RAD51 reduces risk of squamous cell carcinoma of the head and neck and interacts with a P53 codon 72 variant
1 Department of Epidemiology
2 Department Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
* To whom correspondence should be addressed. Tel: +1 713 792 3020; Fax: +1 713 563 0999; Email: qwei{at}mdanderson.org
RAD51 participates in homologous recombination (HR) repair of double-stranded DNA breaks (DSBs) that may cause genomic instability and cancer. Two single-nucleotide polymorphisms (SNPs) and three P53 binding sites have been found in the RAD51 promoter and 5' untranslated region. We hypothesized that RAD51 and P53 SNPs may interact and alter risk of squamous cell carcinoma of the head and neck (SCCHN) and we genotyped for RAD51 135G>C and 172G>T and P53 Arg72Pro SNPs in 716 SCCHN patients and 719 matched controls (all non-Hispanic whites) and evaluated their effects on gamma radiation-induced mutagen sensitivity. We found that RAD51 172TT homozygotes had a significantly decreased risk [adjusted odds ratio (OR) = 0.66, 95% confidence interval (CI) = 0.50–0.87] of SCCHN, compared with carriers of other genotypes, particularly in P53 Arg72Arg homozygotes (adjusted OR = 0.60, 95% CI = 0.41–0.89) (homogeneity test P = 0.047), although no alterations in the risk were associated with the RAD51 135G>C and P53 Arg72Pro SNPs. Consistent with a protective effect of the 172TT genotype, significantly fewer gamma radiation-induced chromatid breaks per cell were present in 172TT homozygotes (mean ± SD = 0.36 ± 0.13) than in subjects with other genotypes (mean ± SD = 0.46 ± 0.13, P < 0.001) among 148 control subjects we tested. The finding that the functional RAD51 172G>T SNP, particularly in the presence of the P53 Arg72Arg genotype, may be a marker of susceptibility to SCCHN needs to be validated by larger studies of different ethnic populations.
Key Words: Case-control study • DNA repair • Genetic susceptibility • Molecular epidemiology • Mutagen sensitivity
Abbreviations: AIC, Akaike's information criterion; b/c, breaks per cell; CI, confidence interval; DSB, DNA double-strand break; HR, homologous recombination; HWE, Hardy–Weinberg equilibrium; LD, linkage disequilibrium; MAF, minor allele frequency; NIH, National Institutes of Health; OR, odds ratio; PCR, polymerase chain reaction; SNP, single-nucleotide polymorphism; SCCHN, squamous cell carcinoma of the head and neck; UTR, untranslated region
Received September 4, 2006; revised November 9, 2006; accepted November 11, 2006.