Influence of polymorphisms at loci encoding DNA repair proteins on cancer susceptibility and G2 chromosomal radiosensitivity.
Sixteen candidate polymorphisms (13 SNPs and 3 microsatellites) in nine genes from four DNA repair pathways were examined in 83 subjects, comprising 23 survivors of childhood cancer, their 23 partners, and 37 offspring, all of whom had previously been studied for G(2) chromosomal radiosensitivity. Genotype at the Asp148Glu SNP site in the APEX gene of the base excision repair (BER) pathway was associated with childhood cancer in survivors (P = 0.001, significant even after multiple test adjustment), due to the enhanced frequency of the APEX Asp148 allele among survivors in comparison to that of their partners. Analysis of variance (ANOVA) of G(2) radiosensitivity in the pooled sample, as well as family-based association test (FBAT) of the family-wise data, showed sporadic suggestions of associations between G(2) radiosensitivity and polymorphisms at two sites (the Thr241Met SNP site in the XRCC3 gene of the homologous recombinational pathway by ANOVA, and the Ser326Cys site in the hOGG1 gene of the BER pathway by FBAT analysis), but neither of these remained significant after multiple-test adjustment. This pilot study provides an intriguing indication that DNA repair gene polymorphisms may underlie cancer susceptibility and variation in radiosensitivity.
Wilding
Craig S
CS
Genetics Department, Westlakes Research Institute, Westlakes Science and Technology Park, Moor Row, Cumbria, United Kingdom.
Curwen
Gillian B
GB
Tawn
E Janet
EJ
Sheng
Xiaohua
X
Winther
Jeanette F
JF
Chakraborty
Ranajit
R
Boice
John D
JD
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000704:Analysis of Variance; D002648:Child; D045647:DNA Glycosylases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D016195:G2 Phase; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics / Q000502:physiology; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011836:Radiation Tolerance / Q000235:genetics*
D004268:DNA-Binding Proteins; C110901:X-ray repair cross complementing protein 3; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase