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Tawn E.J.,University of Central Lancashire | Rees G.S.,Westlakes Research Institute | Leith C.,Westlakes Research Institute | Winther J.F.,Danish Cancer Society | And 9 more authors.
International Journal of Radiation Biology | Year: 2011

Purpose: To investigate minisatellite germline mutation rates in survivors of childhood and young adult cancer who received radiotherapy. Materials and methods: DNA samples from 100 families, where one parent was a cancer survivor, were analysed for mutations at eight hypervariable minisatellite loci (B6.7, CEB1, CEB15, CEB25, CEB36, MS1, MS31, MS32) by Southern hybridisation. Results: No significant difference was observed between the paternal mutation rate of 5.6% in exposed fathers with a mean preconceptional testicular dose of 1.23 Gy (56 mutations in 998 informative alleles) and that of 5.8% in unexposed fathers (17 in 295 informative alleles). Subgrouping the exposed fathers into dose groups of <0.10 Gy, 0.10-0.99 Gy, 1.00-1.99 Gy, ≥2.00 Gy revealed no significant differences in paternal mutation rate in comparison with the unexposed fathers. Maternal mutation rates of 1.6% in cancer survivor mothers with a mean preconceptional ovarian dose of 0.58 Gy (five mutations in 304 informative alleles) and 2.1% in unexposed mothers (21 in 987 informative alleles) were not significantly different. There were no differences in minisatellite mutation rates associated with treatment with chemotherapeutic agents. Conclusions: This study provides evidence that preconception radiotherapy for childhood or early adulthood cancer does not increase the germline minisatellite mutation rate. © 2011 Informa UK, Ltd.


Curwen G.B.,Westlakes Research Institute | Cadwell K.K.,Westlakes Research Institute | Cadwell K.K.,Northumbria University | Tawn E.J.,University of Manchester | And 3 more authors.
Mutagenesis | Year: 2012

Intra-individual variation in G2 chromosomal radiosensitivity was examined by repeatedly taking blood samples from two individuals. Two healthy female volunteers provided a total of 44 blood samples, Donor 1 gave 28 samples in four time periods between 2001 and 2006 and Donor 2 gave 16 samples in two of the same time periods. Lymphocytes were cultured for 72 h prior to irradiation with 0.5 Gy, 300 kV X-rays. Colcemid was added 30 min post-irradiation. Cultures were harvested 90 min post-irradiation and analysed for chromatid gaps and breaks. Donor 1 exhibited significant intra-individual variation in G2 chromosomal radiosensitivity for two of the four time periods. Variation was not significant for Period 1 (13 samples, P = 0.111) and Period 2 (six samples, P = 0.311) but was significant for Period 3 (two samples, P = 0.030) and Period 4 (seven samples, P = 0.005). Significant intra-individual variation was observed for both time periods involving Donor 2, these being Period 2 (nine samples, P = 0.002) and Period 4 (seven samples, P < 0.001). The combined data from all time periods exhibited a significant intra-individual variation for Donor 1 (P < 0.001) and Donor 2 (P < 0.001). These findings led to the conclusion that too much reliance should not be placed on the result from a single sample when assessing individual radiosensitivity status. © The Author 2012. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved.


Cadwell K.K.,Westlakes Research Institute | Curwen G.B.,Westlakes Research Institute | Tawn E.J.,University of Central Lancashire | Winther J.F.,Danish Cancer Society | And 2 more authors.
Mutagenesis | Year: 2011

Significant inter-individual variation in G2 chromosomal radiosensitivity, measured as radiation-induced chromatid-type aberrations in the subsequent metaphase, has been reported in peripheral blood lymphocytes of both healthy individuals and a range of cancer patients. One possible explanation for this variation is that it is driven, at least in part, by the efficiency of G2-M checkpoint control. The hypothesis tested in the current analysis is that increased G2 chromosomal radiosensitivity is facilitated by a less efficient G2-M checkpoint. The study groups comprised 23 childhood and adolescent cancer survivors, their 23 partners and 38 of their offspring (Group 1) and 29 childhood and young adult cancer survivors (Group 2). Following exposure to 0.5 Gy of 300 kV X-rays, lymphocyte cultures were assessed for both G2 checkpoint delay and G2 chromosomal radiosensitivity. In Group 1, the extent of G2 checkpoint delay was measured by mitotic inhibition. No statistically significant differences in G2 checkpoint delay were observed between the cancer survivors (P = 0.660) or offspring (P = 0.171) and the partner control group nor was there any significant relationship between G2 checkpoint delay and G2 chromosomal radiosensitivity in the cancer survivors (P = 0.751), the partners (P = 0.634), the offspring (P = 0.824) or Group 1 taken as a whole (P = 0.379). For Group 2, G2 checkpoint delay was assessed with an assay utilising premature chromosome condensation to distinguish cell cycle stage. No significant relationship between G2 checkpoint delay and G2 chromosomal radiosensitivity was found (P = 0.284). Thus, this study does not support a relationship between G2-M checkpoint efficiency and variation in G2 chromosomal radiosensitivity. © The Author 2010. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved.


Curwen G.B.,Westlakes Research Institute | Murphy S.,University of Central Lancashire | Tawn E.J.,University of Central Lancashire | Winther J.F.,Danish Cancer Society | And 2 more authors.
Environmental and Molecular Mutagenesis | Year: 2011

The previously reported association of the APEX Asp148Glu single nucleotide polymorphism (SNP) with cancer, and the suggestion of associations of the XRCC3 Thr241Met and hOGG1 Ser326Cys SNP sites with G2 chromosomal radiosensitivity were investigated in a new study of 30 childhood and young adult cancer survivors, their 30 partners, and 55 offspring. An additional SNP, hOGG1 Arg46Gln was also analyzed. Data on G2 chromosomal radiosensitivity was available on 29 of the families including 53 offspring. No significant associations of genotype with cancer or G2 chromosomal radiosensitivity were observed. Copyright © 2010 Wiley-Liss, Inc.


Curwen G.B.,Westlakes Research Institute | Cadwell K.K.,Westlakes Research Institute | Winther J.F.,Danish Cancer Society | Janet Tawn E.,University of Central Lancashire | And 9 more authors.
International Journal of Radiation Biology | Year: 2010

Purpose:To investigate the relationship between chromosomal radiosensitivity and early-onset cancer under the age of 35 years and to examine the heritability of chromosomal radiosensitivity. Materials and methods:Peripheral blood lymphocytes were cultured for 72 hours prior to being irradiated with 0.5 Gy, 300 kV X-rays. Colcemid was added to cultures 30min post-irradiation. Cultures were harvested 90min post-irradiation and analysed for chromatid gaps and breaks. Heritability was estimated using Sequential Oligogenic Linkage Analysis Routines (SOLAR) software and by segregation analysis. Results:Elevated radiosensitivity was seen for seven out of 29 (24.1%) cancer survivors, three out of 29 (10.3%) partners and 10 out of 53 (20.8%) offspring. Although the proportion of individuals displaying enhanced radiosensitivity was twice as high in both the cancer survivor and offspring groups than the partner controls, neither reached statistical significance. Heritability analysis of the radiosensitive phenotype suggested 57.9-78.0% of the variance could be attributed to genetic factors. Conclusion:An association between G2 chromosomal radiosensitivity and childhood and young adult cancer is suggested but was not statistically significant. In contrast, there is strong evidence for heritability of the radiosensitive phenotype. The cancer survivors included a broad range of malignancies and future studies should focus on specific cancers with known or likely faults in deoxyribonucleic acid (DNA) damage recognition and repair mechanisms. © 2010 Informa UK, Ltd.


Curwen G.B.,Westlakes Research Institute | Curwen G.B.,University of Manchester | Janet Tawn E.,University of Manchester | Cadwell K.K.,Westlakes Research Institute | And 4 more authors.
Radiation Research | Year: 2012

A multicolored FISH (mFISH) technique was used to characterize the cytogenetic damage associated with exposure to α-particle radiation with particular emphasis on the quality and quantity that is likely to be transmitted through cell division to descendant cells. Peripheral blood lymphocytes were irradiated in vitro with 238Pu α particles with a range of mean doses up to 936 mGy and were cultured for 47 h. The dose responses for total aberrant cells, stable and unstable cells, and cells with one simple chromosome aberration and multiple chromosome aberrations were predominantly linear for doses that resulted in cell nuclei receiving a single α-particle traversal. However, there was a decrease per unit dose in aberrant cells of all types at higher doses because of cells increasingly receiving multiple traversals. The proportion of radiation-induced aberrant cells containing multiple aberrations ranged from 48 to 74 with little evidence of dose dependency. Ninety-one percent of all cells with multiple aberrations were classified as unstable. Resolving the chromosome rearrangements into simple categories resulted in a linear dose response for dicentrics of 24.9 ± 3.3 × 10-2 per Gy. The predominant aberration in stable transmissible cells was a single translocation with a dose response for predominantly single hit cell nuclei of 4.1 ± 1.3 × 10-2 per Gy. Thus, translocations are the most likely aberration to be observed in peripheral blood lymphocytes from individuals with incorporated α-emitting radionuclides resulting in long-term chronic exposure. © 2012 by Radiation Research Society. All rights of reproduction in any form reserved.


McGeoghegan D.,Westlakes Research Institute | Whaley S.,Westlakes Research Institute | Binks K.,Westlakes Research Institute | Gillies M.,Westlakes Research Institute | And 3 more authors.
Journal of Radiological Protection | Year: 2010

This paper studies the mortality and cancer morbidity of the 470 male workers involved in tackling the 1957 Sellafield Windscale fire or its subsequent cleanup. Workers were followed up for 50 years to 2007, extending the followup of a previously published cohort study on the Windscale fire by 10 years. The size of the study population is small, but the cohort is of interest because of the involvement of the workers in the accident. Significant excesses of deaths from diseases of the circulatory system (standardised mortality ratio (SMR) = 120, 95% CI = 103-138; 194 deaths) driven by ischaemic heart disease (IHD) (SMR = 133, 95% CI = 112-157, 141 deaths) were found when compared with the population of England and Wales but not when compared with the population of Northwest England (SMR = 105, 95% CI = 90-120 and SMR = 115, 95% CI = 97-136 respectively). When compared with those workers in post at the time of the fire but not directly involved in the fire the mortality rate from IHD among those involved in tackling the fire was raised but not statistically significantly (rate ratio (RR) = 1.11, 95% CI = 0.92-1.33). A RR of 1.11 is consistent with an excess relative risk of 0.65 Sv-1 as reported in an earlier study of non-cancer mortality in the British Nuclear Fuels plc cohort of which these workers are a small but significant part. There was a statistically significant difference in lung cancer mortality (RR = 2.18, 95% CI = 1.05- 4.52) rates between workers who had received higher recorded external doses during the fire and those who had received lower external doses. Comparison of the mortality rates of workers directly involved in the accident with workers in post, but not so involved, showed no significant differences overall. On the basis of the use of a propensity score the average effect of involvement in the Windscale fire on all causes of death was -2.13% (se = 3.64%, p = 0.56) though this difference is not statistically significant. The average effect of involvement in the Windscale fire was -5.53% (se = 3.81, p = 0.15) for all cancers mortality and 6.60% (se = 4.03%, p = 0.10) for IHD mortality though neither figure was statistically significant. This analysis of the mortality and cancer morbidity experience of those Sellafield workers involved in the 1957 Windscale fire does not reveal any measurable effect of the fire upon their health. Although this study has low statistical power for detecting small adverse effects, due to the relatively small number of workers, it does provide reassurance that no significant health effects are associated with the 1957 Windscale fire even after 50 years of follow-up. © 2010 IOP Publishing Ltd.


PubMed | Westlakes Research Institute
Type: Journal Article | Journal: Mutagenesis | Year: 2011

Significant inter-individual variation in G(2) chromosomal radiosensitivity, measured as radiation-induced chromatid-type aberrations in the subsequent metaphase, has been reported in peripheral blood lymphocytes of both healthy individuals and a range of cancer patients. One possible explanation for this variation is that it is driven, at least in part, by the efficiency of G(2)-M checkpoint control. The hypothesis tested in the current analysis is that increased G(2) chromosomal radiosensitivity is facilitated by a less efficient G(2)-M checkpoint. The study groups comprised 23 childhood and adolescent cancer survivors, their 23 partners and 38 of their offspring (Group 1) and 29 childhood and young adult cancer survivors (Group 2). Following exposure to 0.5 Gy of 300 kV X-rays, lymphocyte cultures were assessed for both G(2) checkpoint delay and G(2) chromosomal radiosensitivity. In Group 1, the extent of G(2) checkpoint delay was measured by mitotic inhibition. No statistically significant differences in G(2) checkpoint delay were observed between the cancer survivors (P = 0.660) or offspring (P = 0.171) and the partner control group nor was there any significant relationship between G(2) checkpoint delay and G(2) chromosomal radiosensitivity in the cancer survivors (P = 0.751), the partners (P = 0.634), the offspring (P = 0.824) or Group 1 taken as a whole (P = 0.379). For Group 2, G(2) checkpoint delay was assessed with an assay utilising premature chromosome condensation to distinguish cell cycle stage. No significant relationship between G(2) checkpoint delay and G(2) chromosomal radiosensitivity was found (P = 0.284). Thus, this study does not support a relationship between G(2)-M checkpoint efficiency and variation in G(2) chromosomal radiosensitivity.


PubMed | Westlakes Research Institute
Type: Journal Article | Journal: Radiation research | Year: 2012

A multicolored FISH (mFISH) technique was used to characterize the cytogenetic damage associated with exposure to -particle radiation with particular emphasis on the quality and quantity that is likely to be transmitted through cell division to descendant cells. Peripheral blood lymphocytes were irradiated in vitro with (238)Pu particles with a range of mean doses up to 936 mGy and were cultured for 47 h. The dose responses for total aberrant cells, stable and unstable cells, and cells with one simple chromosome aberration and multiple chromosome aberrations were predominantly linear for doses that resulted in cell nuclei receiving a single -particle traversal. However, there was a decrease per unit dose in aberrant cells of all types at higher doses because of cells increasingly receiving multiple traversals. The proportion of radiation-induced aberrant cells containing multiple aberrations ranged from 48 to 74% with little evidence of dose dependency. Ninety-one percent of all cells with multiple aberrations were classified as unstable. Resolving the chromosome rearrangements into simple categories resulted in a linear dose response for dicentrics of 24.9 3.3 10(-2) per Gy. The predominant aberration in stable transmissible cells was a single translocation with a dose response for predominantly single hit cell nuclei of 4.1 1.3 10(-2) per Gy. Thus, translocations are the most likely aberration to be observed in peripheral blood lymphocytes from individuals with incorporated -emitting radionuclides resulting in long-term chronic exposure.


PubMed | Westlakes Research Institute
Type: Journal Article | Journal: Mutagenesis | Year: 2012

Intra-individual variation in G(2) chromosomal radiosensitivity was examined by repeatedly taking blood samples from two individuals. Two healthy female volunteers provided a total of 44 blood samples, Donor 1 gave 28 samples in four time periods between 2001 and 2006 and Donor 2 gave 16 samples in two of the same time periods. Lymphocytes were cultured for 72 h prior to irradiation with 0.5 Gy, 300 kV X-rays. Colcemid was added 30 min post-irradiation. Cultures were harvested 90 min post-irradiation and analysed for chromatid gaps and breaks. Donor 1 exhibited significant intra-individual variation in G(2) chromosomal radiosensitivity for two of the four time periods. Variation was not significant for Period 1 (13 samples, P = 0.111) and Period 2 (six samples, P = 0.311) but was significant for Period 3 (two samples, P = 0.030) and Period 4 (seven samples, P = 0.005). Significant intra-individual variation was observed for both time periods involving Donor 2, these being Period 2 (nine samples, P = 0.002) and Period 4 (seven samples, P < 0.001). The combined data from all time periods exhibited a significant intra-individual variation for Donor 1 (P < 0.001) and Donor 2 (P < 0.001). These findings led to the conclusion that too much reliance should not be placed on the result from a single sample when assessing individual radiosensitivity status.

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