Genetic Consequences of Therapies for Cancer

癌症治疗的遗传后果

• 批准号: 7122129
• 负责人: JOHN Dunning BOICE
• 金额: $ 61.28万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-12 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7122129
• 关键词: Scandinavian country; cancer risk; child (0-11); clinical research; congenital disorders; disease /disorder proneness /risk; embryo /fetus death; family genetics; fertility; gene mutation; genetic polymorphism; human data; human subject; infant mortality; long term survivor; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer radiation therapy; ovary; radiation therapy dosage; testis; therapy adverse effect; young adult human (21-34)

DESCRIPTION (provided by applicant): Our objective is to conduct a large-scale retrospective cohort study of the offspring of survivors of childhood and early onset 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.

描述（由申请人提供）：我们的目标是对儿童期和早期癌症幸存者后代进行大规模回顾性队列研究，并确定在测试系统中具有诱变的治疗疗法，放射和化学疗法的程度为了不利的健康结果或其他定义为癌症的遗传作用，出生缺陷，死产，新生儿和所有其他早期死亡。年轻人对癌症的治疗变得越来越成功。例如，据估计，今天仅在美国，据估计，有270,000多名儿童癌症幸存者还活着，许多人能够拥有自己的孩子。因此，治疗治疗对癌症幸存者遗传疾病的可能影响变得越来越重要。但是，对这些治疗的遗传后果或是否可以传播到其后代的遗传后果几乎没有理解。此外，在晚期影响的研究中，经常忽略被诊断出20至34岁癌症的年轻人。尽管几乎没有证据表明诱变疗法会导致跨代作用，但很少有研究对睾丸或卵巢的治疗剂量造成的风险。 1943年在丹麦和1952年之后，所有被诊断出患有35岁以下癌症的人都将及其兄弟姐妹及其兄弟姐妹一起确定。在10,000名幸存到生殖年龄的癌症儿童中，据估计有3,000名已成为5,600名儿童的父母。在38,000名被诊断为癌症年轻人的患者中，有25,000名幸存下来，并在癌症诊断后有14,000名儿童。因此，可以研究19,600个癌症幸存者的后代。兄弟姐妹及其后代的名册将用于比较目的。丹麦和芬兰的后代队列将与鉴定癌症，出生缺陷，死产以及新生儿和其他死亡的结果注册界有关。将获得癌症幸存者的病历，并摘要放射记录和化学疗法信息。将计算针对性腺的辐射剂量（女性幸存者的子宫），并评估治疗疗法的遗传后果。许多癌症幸存者对放射或化学疗法的性腺暴露将很高，并且低于不孕症的阈值。血样将从幸存者，他们的配偶和后代样本中收集，以检查许多与癌症易感性有关的机械过程，以及治疗对患者本身和后代潜在健康结果的影响。 200个家庭将捐赠淋巴细胞和DMA进行储存和实验室分析，其中包括G2辐射测定法以评估染色体辐射敏感性（这可能与DMA损伤反应/修复基因的改变有关）并确定是否可以继承这种敏感性；评估特定修复基因的变体多态性的特定修复基因；和评估Minisatellite继承。丹麦的一项试点研究表明，拟议的研究方法是可行的。该研究应有助于回答有关诱变暴露的遗传后果的问题，探索是否可以确定特定癌症的易感性状态和特定的遗传多态性，并评估对未来一代人的遗传易感性或遗传损害的程度。