Does Cancer Treatment in Childhood Induce Transgenerational Genetic Damage?
Authors: Jeanette F. Winther, Jørgen H. Olsen
Journal: Journal of Clinical Oncology (2011)

“The genetic heritage of the human species resides in our germ cells (egg and sperm), and it is our collective stewardship responsibility to protect the genomic integrity of germ cells to assure that today’s societal actions do not increase the burden of abnormal pregnancies and genetic diseases for future generations.” That is how the 2004 Workshop on Assessing Human Germ Cell Mutagenesis (Jackson Laboratory, Bar Harbor, ME) began. Studies of the offspring of cancer survivors were explicitly recommended as a means of addressing the key fundamental questions: “Can we detect human germ cell mutagens?” and “What are the risks to future generations?” In genetic counseling on mutagenic effects on the human gonad, the ultimate concern is hereditary disease. Does cancer treatment induce damage of human germ cells? Does it cause actual disease in the offspring, or mutational events of no clinical significance? These concerns are voiced not only by geneticists, pediatric oncologists, and other specialists in this field but also by the former patients themselves. Childhood cancer survivors worry about whether their children will be healthy or whether they might pass on a genetic risk or predisposition for cancer. In the article that accompanies this editorial, Signorello et al report on single-gene defects, cytogenetic abnormalities, and congenital malformations among the children of childhood cancer survivors with the overall aim of trying to answer these questions by using the unique resources within the North American Childhood Cancer Survivor Study (CCSS). The risk of these selected outcomes was studied in 4,699 children of 2,755 cancer survivors. Exposure data were based on medical record abstraction that included organ radiation dosimetry and alkylating agent dose scores and took into account exposure to combinations of different drugs and doses. Outcomes were based on self-reports but were validated by an expert panel and medical record review, resulting in a total of 129 children with at least one reported anomaly, for a prevalence of 2.7%. Parental exposure to radiation or alkylating agents did not increase the risk of congenital anomalies in the offspring, nor did ovarian or testicular radiation dose. The results of this study are consistent with the findings of the pioneering study of the pregnancies and offspring of childhood cancer survivors that was performed by Li et al in 1979, as well as those of the vast majority of subsequent studies of adverse health outcomes in the offspring of childhood and adolescent cancer survivors, including several large population-based studies. Previous studies considered outcomes with a high genetic component, such as chromosomal abnormalities, single-gene disorders, and congenital malformations, as potential indicators of transmitted germline damage, but spontaneous abortions, cancer, stillbirths, and sex ratio alterations have also been used as measures of genetic disease in the next generation. A major limitation of these studies, however, has been lack of detailed information on treatment such as gonadal radiation and alkylating agent doses. The findings of the report by Signorello et al also agree with those of a Danish case-cohort study that defined genetic disease as chromosomal abnormalities, congenital malformations, stillbirths, and neonatal deaths. This study was based on all childhood cancer survivors and their children in Denmark and obtained information on both study subjects and outcomes from nationwide population-based health registries. This population-based setting with virtually complete follow-up of study subjects resulted in a study that was less susceptible to biases that are associated with participation, response, recall, and reporting. Although design and methodology differed between the two studies, there were remarkable similarities in the findings—similarities that encourage closer collaboration between the two research centers in the future. Both studies were able to implement a gold standard approach for exposure assessment, in which the chemotherapy received and preconception doses of radiation to the ovary and testes were quantified from medical records and actual radiotherapy schemes and related to genetic disease. Computation of individual gonadal doses with similar mean ovarian (1.19 Gy in CCSS and 1.16 Gy in Denmark) and testicular doses (0.48 Gy and 0.41 Gy, respectively) estimated at MD Anderson Cancer Center in Houston, TX, made it possible for these two studies to be the first studies, to our knowledge, to interpret the epidemiologic results for the selected outcomes in light of dose-response evaluations. The authors of both studies (three individuals were authors in both studies) concluded that preconception cancer treatment in childhood did not lead to transgenerational germ cell mutations that resulted in disease in the next generation. Doseresponse findings have previously been reported on stillbirths and neonatal deaths among the children of female CCSS participants with estimated radiation doses to the ovaries and uterus—findings that were interpreted as probably related to radiation-induced uterine damage. Consistent with the results of the epidemiologic studies, a study including 100 Danish survivors of childhood and young adult cancer, their 170 children, and the other parent provided no evidence that preconception radiotherapy increased the germline minisatellite mutation rate. These reassuring findings for childhood cancer survivors who are subsequently able to have children strongly indicate that cancer treatment—at least the agents and doses to which these survivors were exposed—does not induce transmissible mutations in human spermatogonial stem cells or resting oocytes. The results and the clinical information provided by these large studies can be used in counseling cancer survivors who wish and are able to have children of their own Editorials