New germline mutations in the hypervariable minisatellite CEB1 in the parents of children with leukaemia

Davies, Bryn G.; Hussain, Adiba; Ring, Susan M.; Birch, Jillian M; Eden, Tim; Reeves, M. M.; Dubrova, Yuri E.; Taylor, G. Malcolm

doi:10.1038/sj.bjc.6603706

Cited by 7 publications

(10 citation statements)

References 42 publications

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“…However, the data are less compelling from human studies. In fact, findings are largely equivocal in relation to paternal exposure to radiation and a subsequent increase in germline alterations 13‐16 . The association we observed in relation to paternal exposure to medical radiation and bilateral retinoblastoma in offspring supports the observation that exposure to gonadal radiation from medical imaging procedures could lead to de novo germline alterations in a subset of individuals.…”

Section: Discussionsupporting

confidence: 68%

Medical radiation exposure and risk of sporadic retinoblastoma

Shakeel

Pace

Chambers

et al. 2020

Pediatric Blood & Cancer

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Background: While there is evidence that parental exposure to medical radiation is associated with increased risk of sporadic bilateral retinoblastoma in offspring, this association has not been confirmed. Additionally, the relationship between paternal and maternal exposures and sporadic unilateral retinoblastoma has not been fully investigated. Procedure: Data were obtained from two large multicenter case-control studies of retinoblastoma. For the paternal analyses, 268 bilateral cases, 155 unilateral cases, and 358 controls were included. For the maternal analyses, 298 bilateral cases, 184 unilateral cases, and 404 controls were included. Logistical regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) to evaluate the associations between parental exposures to medical radiation and sporadic retinoblastoma, while adjusting for potential confounders. Results: Paternal exposure to medical radiation was not significantly associated with sporadic bilateral retinoblastoma in offspring. However, increasing paternal exposure to gonadal radiation was associated with increased risk of unilateral retinoblastoma (P-trend = .03). Maternal history of upper and lower gastrointestinal (GI) series was associated with bilateral retinoblastoma (OR = 1.9, 95% CI: 1.1-3.2 and OR = 6.9, 95% CI: 2.9-16.4, respectively). However, there was no association between maternal exposure to medical radiation and unilateral retinoblastoma in offspring. Conclusion: Our investigation adds to the evidence that medical radiation exposure in fathers as well as mothers prior to pregnancy may increase the risk of germline alterations leading to the development of retinoblastoma in their offspring. However, our findings could point to a more complex etiological framework for this important pediatric malignancy.

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Section: Discussionsupporting

confidence: 68%

Medical radiation exposure and risk of sporadic retinoblastoma

Shakeel

Pace

Chambers

et al. 2020

Pediatric Blood & Cancer

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“…DNA was transferred to a nylon membrane (Hybond‐XL; Amersham Pharmacia, Piscataway, NJ, USA) by Southern blotting, where it was fixed by ultraviolet cross‐linking. DNA fingerprints were generated by sequential hybridization with 32 P‐labeled (Perkin‐Elmer, Waltham, MA, USA) synthetic minisatellite probes B6.7 (6) and CEB1 (26), and they were visualized by using FujiFilm imaging system FLA‐3000 (Raytest, Straubenhardt, Germany). Scoring was performed without knowledge of exposure and verified by a second observer.…”

Section: Methodsmentioning

confidence: 99%

Paternal lifestyle as a potential source of germline mutations transmitted to offspring

et al. 2013

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Paternal exposure to high levels of radioactivity causes heritable germline minisatellite mutations. However, the effect of more general paternal exposures, such as cigarette smoking, on germline mutations remains unexplored. We analyzed two of the most commonly used minisatellite loci (CEB1 and B6.7) to identify germline mutations in blood samples of complete mother-father-child triads from the Norwegian Mother and Child Cohort Study (MoBa). The presence of mutations was subsequently related to general lifestyle factors, including paternal smoking before the partner became pregnant. Paternally derived mutations at the B6.7 locus (mutation frequency 0.07) were not affected by lifestyle. In contrast, high gross yearly income as a general measure of a healthy lifestyle coincided with low-mutation frequencies at the CEB1 locus (P=0.047). Income was inversely related to smoking behavior, and paternally derived CEB1 mutations were dose dependently increased when the father smoked in the 6 mo before pregnancy, 0.21 vs. 0.05 in smoking and nonsmoking fathers, respectively (P=0.061). These results suggest that paternal lifestyle can affect the chance of heritable mutations in unstable repetitive DNA sequences. To our knowledge, this is the first study reporting an effect of lifestyle on germline minisatellite mutation frequencies in a human population with moderate paternal exposures.

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“…Similarly, in a forerunner to the present work, no increase in minisatellite mutations was observed in a pilot study of childhood cancer survivors and their families, which compared those survivors treated with radiotherapy with their unexposed partners (Rees et al 2006). Finally, the hypothesis that a proportion of childhood leukaemia cases might be associated with an increase in minisatellite germline mutations resulting from parental exposure could not be sustained, when no increase in inherited germline minisatellite mutations was found in children with leukaemia (Davies et al 2007). …”

Section: Introductionmentioning

confidence: 99%

Germline minisatellite mutations in survivors of childhood and young adult cancer treated with radiation

Tawn¹,

Rees²,

Leith³

et al. 2010

International Journal of Radiation Biology

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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.

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New germline mutations in the hypervariable minisatellite CEB1 in the parents of children with leukaemia

Cited by 7 publications

References 42 publications

Medical radiation exposure and risk of sporadic retinoblastoma

Medical radiation exposure and risk of sporadic retinoblastoma

Paternal lifestyle as a potential source of germline mutations transmitted to offspring

Germline minisatellite mutations in survivors of childhood and young adult cancer treated with radiation

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