Genetic Consequences of Therapies for Cancer

我们的目的是对儿童期和早发性脑卒中幸存者的后代进行大规模的回顾性队列研究 癌症，并确定在何种程度上治愈疗法，辐射和化疗是诱变， 测试系统，有助于不利的健康结果或其他遗传效应，定义为癌症，出生缺陷， 死胎、新生儿和所有其他过早死亡。年轻人的癌症治疗越来越多， 成功例如，据估计，今天在美国有27万多名儿童癌症幸存者。 只有国家和许多国家能够有自己的孩子。因此，治愈性治疗的可能效果 癌症幸存者遗传性疾病的研究变得越来越重要。然而， 这些治疗的遗传后果，或者潜在的易感性是否可以传递给他们， 后代此外，20-34岁被诊断患有癌症的年轻人在最近的研究中经常被忽视。 方面的影响.虽然几乎没有证据表明诱变疗法会导致跨代效应，但很少有研究表明， 研究了睾丸或卵巢的治疗剂量风险。所有35岁以下被诊断患有癌症的人， 1943年在丹麦和1952年后在芬兰将被确定，沿着与他们的兄弟姐妹。在10，000名患有 据估计，在存活到生育年龄的癌症患者中，有3，000人已经成为5，600名儿童的父母。之间 在38,000名年轻人被诊断患有癌症的患者中，25,000人幸存下来，14,000人在癌症后有了孩子 诊断.因此，可以研究19，600名癌症幸存者的后代。兄弟姐妹和他们的后代的名册将是 用于比较目的。丹麦和芬兰的后代队列将与结局登记研究相关联 确定癌症、出生缺陷、死产、新生儿和其他死亡。癌症幸存者的医疗记录 获取放射治疗记录和化疗信息。生殖腺（和子宫）的辐射剂量 女性幸存者），并将评估治愈性治疗的遗传后果。性腺 许多癌症幸存者的放射或化疗暴露将很高， 不孕将从幸存者、他们的配偶和后代的样本中收集血液样本， 与癌症易感性和治疗对潜在健康的影响相关的机械过程的数量 患者自身及其后代的结果。200个家庭将捐赠淋巴细胞和DMA， 储存和实验室分析，包括G2辐射分析，以评估染色体辐射敏感性（ 可能与DMA损伤反应/修复基因的改变有关），并确定这种敏感性是否可以 遗传;评估特异性修复基因，如XRCC 1，变异多态性;和评估小卫星 传承在丹麦进行的一项试点研究表明，拟议的研究方法是可行的。这项研究应该 帮助回答有关诱变暴露的遗传后果的问题，探索易感性是否 可以鉴定特定癌症的状态和赋予易感性的特定遗传多态性，并评估 经鉴定的遗传易感性或遗传损伤程度可遗传给后代。

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.