Influence of polymorphisms of loci encoding DNA repair proteins on cancer susceptibility and G₂ chromosomal radiosensitivity

Sixteen condidate polymorphisms (13 SNPs ond 3 microsotellites) 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 G₂ chromosomal radiosensitivity. Genotype at the Asp 148Glu 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 G₂ 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 Thr241-Met 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.