G₂ chromosomal radiosensitivity in childhood and adolescent cancer survivors and their offspring

Human chromosome abnormalities--Etiology;Human chromosomes--Effect of radiation on;Radiation tolerance;Cancer--Susceptibility;DNA repair

Curwen, Gillian B. ; Bryant, Peter Edward ; Bryant, Peter Edward

University:University of St Andrews

Department:Biology (School of)

关键词: Human chromosome abnormalities--Etiology;    Human chromosomes--Effect of radiation on;    Radiation tolerance;    Cancer--Susceptibility;    DNA repair;   

Others  :  https://research-repository.st-andrews.ac.uk/bitstream/handle/10023/425/Gillian%20Curwen%20PhD%20thesis.pdf?sequence=1&isAllowed=y

来源: DR-NTU

【 摘 要 】

It is increasingly recognised that individual risk of cancer may be related to geneticallydetermined differences in the ability of cells to identify and repair DNA damage. Cellcycle based assays of chromosomal radiosensitivity provide the greatest power fordiscriminating differences in response to DNA damage and it has been suggested thatindividuals who are genetically susceptible to cancer show increased chromosomalradiosensitivity. The relationship between chromosomal radiosensitivity and early onsetcancer was investigated in a population of Danish survivors of childhood and adolescentcancer and a control group comprising of their partners using the G₂ assay of chromosomalradiosensitivity. Heritability was also examined in the offspring.No significant differences in radiosensitivity profiles were found between partner controlsand either the cancer survivors or offspring. However, when compared to the WestlakesResearch Institute control population, significant differences were observed with thecancer survivors (P = 0.002) and offspring (P < 0.001), supporting an association ofchromosomal radiosensitivity with cancer predisposition. Heritability studies suggestedthe majority of phenotypic variance of chromosomal radiosensitivity was attributable to aputative major gene locus with dominant effect.Since G2 chromosomal radiosensitivity indirectly measures the ability of cells to repairDNA damage induced by ionising radiation exposure, variants in DNA repair genes mayexplain inter-individual variation observed. Sixteen polymorphisms in nine genes fromfour DNA repair pathways were investigated. Genotype frequencies at the Asp148Glupolymorphism were associated with childhood cancer in survivors. Analysis of variance and FBAT analysis suggested significant associations at both the Thr241Met andSer326Cys polymorphism sites with G₂ radiosensitivity, but neither remained significantafter multiple-test adjustment.This study invites further exploration of the predictive capacity of G₂ chromosomalradiosensitivity in cancer predisposition. Clearly, further work is needed to correlateradiosensitivity with genetic polymorphisms, which may underlie cancer susceptibility andvariation in radiosensitivity.