Our objective is to conduct a large-scale retrospective cohort study of the offspring of survivors of childhood and earlyonset cancer and determine the extent to which curative therapies, radiation and chemotherapy that are mutagenic in test systems, contribute to adverse health outcomes or other inherited effects defined as cancer, birth defects, stillbirths, neonatal and all other premature deaths. The treatment of cancer among the young has become increasingly successful. For example, over 270,000 survivors of childhood cancer are estimated to be alive today in the United States alone and many are able to have children of their own. Consequently, the possible effects of curative treatments on inherited disorders in cancer survivors are becoming increasingly important. However, there is little understanding of the genetic consequences of these treatments or whether underlying susceptibility can be transmitted to their offspring. Further, young adults diagnosed with cancer at ages 20-34 years are often overlooked in studies of late effects. While there is little evidence that mutagenic therapies can result in transgenerational effects, few studies have looked at risk in terms of treatment dose to testes or ovaries. All persons diagnosed with cancer under age 35 after 1943 in Denmark and after 1952 in Finland will be identified, along with their siblings. Among the 10,000 children with cancer who survived to reproductive ages, 3,000 are estimated to have become the parents of 5,600 children. Among the 38,000 patients diagnosed with cancer as young adults, 25,000 survived and had 14,000 children after their cancer diagnosis. Thus, 19,600 offspring of cancer survivors can be studied. Rosters of siblings and their offspring will be developed for comparison purposes. The offspring cohorts in Denmark and Finland will be linked to outcome registries to identify cancer, birth defects, stillbirths and neonatal and other deaths. Medical records of the cancer survivors will be obtained and radiation records and chemotherapy information abstracted. Radiation doses to gonads (and uterus for female survivors) will be calculated, and the genetic consequences of curative therapies will be assessed. The gonadal exposures to radiation or chemotherapy for many cancer survivors will be high and just below the threshold for infertility. Blood samples will be collected from a sample of survivors, their spouses and their offspring to examine a number of mechanistic processes related to cancer predisposition and the effect of therapy on potential health outcomes both in the patients themselves and their offspring. 200 families will donate lymphocytes and DMA for storage and laboratory analyses that will include the G2 radiation assay to assess chromosomal radiosensitivity (that might be related to alterations of DMA damage-response/repair genes) and to determine whether such a sensitivity can be inherited;evaluation of specific repair genes, eg, XRCC1, for variant polymorphisms;and evaluation of minisatellite inheritance. A pilot study in Denmark has indicated that the proposed research approach is feasible. The study should help answer questions regarding the genetic consequences of mutagenic exposures, explore whether susceptibility states and specific genetic polymorphisms conferring susceptibility can be identified for specific cancers, and evaluate the extent to whtch-identifled genetic susceptibility or genetic damage can be transmitted to future generations.
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