Genetic effects and radiosensitivity in childhood cancer survivors and their offspring

*John Boice, Vanderbilt University 

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The children of cancer survivors have been studied to learn of possible adverse genetic effects associated with curative treatments of the parents. Unique population-based cohort studies include the entire populations of Denmark and Finland and the major childhood cancer centers in the United States. The Scandinavian countries utilize nationwide registries to identify study subjects and adverse outcomes in an unbiased manner whereas the U.S. studies include validation of self-reported adverse outcomes. The hypothesis is that radiotherapy and specific chemotherapeutic agents used to treat cancer survivors increase the risk for genetic disease in their children. Genetic disease is defined as cytogenetic abnormalities, single gene disorders, birth defects, stillbirths, neonatal deaths and cancer. Another unique feature includes accurate and reproducible reconstruction of radiation dose to the testes, ovaries and uterus of the cancer survivors who are able to have children. Radiation dose response evaluations have been conducted on malformations, spontaneous abortions, stillbirths, neonatal deaths and preterm births. Blood samples in Denmark and Finland were taken from survivors of cancer, their spouses or partners and their children. Cellular studies address genomic instability, inherited mutations in minisatellite DNA and in mitochondrial DNA, chromosomal radiosensitivity and DNA polymorphic variation, and the occurrence of cytogenetic abnormalities. There were 4,699 children born to the cancer survivors included in the U.S. Childhood Cancer Survivor Study, among whom the prevalence of birth defects did not differ over categories of ovarian dose (mean, 1.19 Gy), or testicular dose (mean, 0.48 Gy); uterine dose to young girls with cancer, however, was associated with an increase in stillbirth, neonatal death and preterm birth. Similar observations were seen among the 1,037 children born to Danish cancer survivors in the Genetic Consequences of Cancer Treatment study where the uterine dose was estimated as 13.5 Gy, mean and 100 Gy, max. Molecular studies found no evidence for inheritance of minisatellite DNA mutations or mitochondrial DNA changes related to gonadal radiation. There was no evidence for genetic instability or clear evidence for G2 chromosomal radiosensitivity, although inheritance of chromosomal radiosensitivity was evident. Our findings do not support concern about heritable genetic changes affecting the risk of malformation, stillbirth and neonatal death in the children of men exposed to testicular irradiation or women exposed to ovarian irradiation. Overall, these findings in population-based studies in two countries are reassuring that the children of cancer survivors are not at high risk of genetic disease apart from known genetic predispositions. However, uterine irradiation of young girls with cancer may have serious adverse effects on their children, and careful management is warranted of pregnancies of women who were given high doses of pelvic irradiation before puberty.