Gamma-radiation sensitivity and polymorphisms in RAD51L1 modulate glioma risk.
BACKGROUND
DNA strand breaks pose the greatest threat to genomic stability. Genetically determined mutagen sensitivity predisposes individuals to a variety of cancers, including glioma. However, polymorphisms in DNA strand break repair genes that may determine mutagen sensitivity are not well studied in cancer risk, especially in gliomas.


METHODS
We correlated genotype data for tag single-nucleotide polymorphisms (tSNPs) of DNA strand break repair genes with a gamma-radiation-induced mutagen sensitivity phenotype [expressed as mean breaks per cell (B/C)] in samples from 426 glioma patients. We also conducted analysis to assess joint and haplotype effects of single-nucleotide polymorphisms (SNPs) on mutagen sensitivity. We further validate our results in an independent external control group totaling 662 subjects.


RESULTS
Of the 392 tSNPs examined, we found that mutagen sensitivity was modified by one tSNP in the EME2 gene and six tSNPs in the RAD51L1 gene (P < 0.01). Among the six RAD51L1 SNPs tested in the validation set, one (RAD51L1 rs2180611) was significantly associated with mutagen sensitivity (P = 0.025). Moreover, we found a significant dose-response relationship between the mutagen sensitivity and the number of adverse tSNP genotypes. Furthermore, haplotype analysis revealed that RAD51L1 haplotypes F-A (zero adverse allele) and F-E (six adverse alleles) exhibited the lowest (0.42) and highest (0.93) mean B/C values, respectively. A similar dose-response relationship also existed between the mutagen sensitivity and the number of adverse haplotypes.


CONCLUSIONS
These results suggest that polymorphisms in and haplotypes of the RAD51L1 gene, which is involved in the double-strand break repair pathway, modulate gamma-radiation-induced mutagen sensitivity.
Liu
Yanhong
Y
Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Shete
Sanjay
S
Wang
Li-E
LE
El-Zein
Randa
R
Etzel
Carol J
CJ
Liang
Fu-Wen
FW
Armstrong
Georgina
G
Tsavachidis
Spyros
S
Gilbert
Mark R
MR
Aldape
Kenneth D
KD
Xing
Jinliang
J
Wu
Xifeng
X
Wei
Qingyi
Q
Bondy
Melissa L
ML
D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000209:etiology / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005720:Gamma Rays / Q000009:adverse effects*; D005910:Glioma / Q000209:etiology / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk
D004268:DNA-Binding Proteins; C413002:RAD51B protein, human