G₂ chromosomal radiosensitivity in childhood and adolescent cancer survivors and their offspring
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It is increasingly recognised that individual risk of cancer may be related to genetically determined differences in the ability of cells to identify and repair DNA damage. Cell cycle based assays of chromosomal radiosensitivity provide the greatest power for discriminating differences in response to DNA damage and it has been suggested that individuals who are genetically susceptible to cancer show increased chromosomal radiosensitivity. The relationship between chromosomal radiosensitivity and early onset cancer was investigated in a population of Danish survivors of childhood and adolescent cancer and a control group comprising of their partners using the G₂ assay of chromosomal radiosensitivity. Heritability was also examined in the offspring. No significant differences in radiosensitivity profiles were found between partner controls and either the cancer survivors or offspring. However, when compared to the Westlakes Research Institute control population, significant differences were observed with the cancer survivors (P = 0.002) and offspring (P < 0.001), supporting an association of chromosomal radiosensitivity with cancer predisposition. Heritability studies suggested the majority of phenotypic variance of chromosomal radiosensitivity was attributable to a putative major gene locus with dominant effect. Since G2 chromosomal radiosensitivity indirectly measures the ability of cells to repair DNA damage induced by ionising radiation exposure, variants in DNA repair genes may explain inter-individual variation observed. Sixteen polymorphisms in nine genes from four DNA repair pathways were investigated. Genotype frequencies at the Asp148Glu polymorphism were associated with childhood cancer in survivors. Analysis of variance and FBAT analysis suggested significant associations at both the Thr241Met and Ser326Cys polymorphism sites with G₂ radiosensitivity, but neither remained significant after multiple-test adjustment. This study invites further exploration of the predictive capacity of G₂ chromosomal radiosensitivity in cancer predisposition. Clearly, further work is needed to correlate radiosensitivity with genetic polymorphisms, which may underlie cancer susceptibility and variation in radiosensitivity.
Thesis, PhD Doctor of Philosophy
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