Genetic Disease in Offspring of Long-Term Survivors of Childhood and Adolescent Cancer

Abstract

Numerous case series have addressed the concern that cancer therapy may damage germ cells, leading to clinical disease in offspring of survivors. None has documented an increased risk. However, the methodological problems of small series make it difficult to draw firm conclusions regarding the potential of cancer treatments to damage the health of future offspring. We conducted a large interview study of adult survivors of childhood cancer treated before 1976. Genetic disease occurred in 3.4% of 2,198 offspring of survivors, compared with 3.1% of 4,544 offspring of controls (P=.33; not significant); there were no statistically significant differences in the proportion of offspring with cytogenetic syndromes, single-gene defects, or simple malformations. A comparison of survivors treated with potentially mutagenic therapy with survivors not so treated showed no association with sporadic genetic disease (P=.49). The present study provides reassurance that cancer treatment using older protocols does not carry a large risk for genetic disease in offspring conceived many years after treatment. With 80% power to detect an increase as small as 40% in the rate of genetic disease in offspring, this study did not do so. However, we cannot rule out the possibility that new therapeutic agents or specific combinations of agents at high doses may damage germ cells.

Sex ratio among offspring of childhood cancer survivors treated with radiotherapy

“…Our study is consistent with the negative findings in the atomic bomb survivor study (Schull et al, 1966) and in two previous studies of survivors of childhood cancer (Hawkins, 1991;Byrne et al, 1998). In the most recent and comprehensive study, Byrne et al evaluated the sex ratio of 2198 offspring born to male and female survivors treated before 1976, compared with that of 4544 offspring born to controls (1.05 vs 1.00, respectively, for males, and 1.01 vs 1.05, respectively, for females).…”

“…Previous studies on the sex ratio among offspring of survivors of childhood cancer have provided little evidence for an alteration following curative therapies (Hawkins, 1991;Byrne et al, 1998). In a large and comprehensive nationwide population-based cohort study using the unique population and health registries within Denmark, we have investigated whether radiotherapy received by childhood cancer patients affected the sex ratio of their offspring.…”

Preconception exposure to mutagens: medical and other exposures to radiation and chemicals

“…After we and others assembled small case series, all with negative findings summarized elsewhere (Mulvihill 1993), our first analytic epidemiologic effort was called the Five Center Study of 2,300 survivors of cancer diagnosed under age 20 years between 1945 and 1975 in five areas of the US (Byrne et al 1998). Genetic disease was defined as a cytogenetic defect, single gene defect, or a common multifactorial birth defect (specifically, those tracked by the US Centers for Disease Control and Prevention).…”

Assessing human germ‐cell mutagenesis in the Postgenome Era: A celebration of the legacy of William Lawson (Bill) Russell

“…Studies of cancer survivors, which are ongoing, are particularly advantageous for germ-cell mutagenesis studies because cancer survivors are increasingly common due to improved therapy regimens, and most importantly, because the timing and dose of their exposure to radiation and/or mutagenic chemicals has been accurately documented in their medical records. Initial analyses of the frequency of birth defects in offspring of cancer survivors have found no significant increases in the prevalence of major congenital malformations compared with the offspring of non-cancer populations [Mulvihill et al, 1987[Mulvihill et al, ,2001Byrne et al, 1998;Fossa et al, 2005]. These data suggest that the agents and doses to which these individuals have been exposed do not induce transmissible mutations in human spermatogonial stem cells or resting oocytes at a frequency high enough to be detected over the background of spontaneous mutations.…”