Genetic Consequences of Therapies for Cancer

癌症治疗的遗传后果

• 批准号: 6928262
• 负责人: JOHN Dunning BOICE
• 金额: $ 63.49万
• 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/6928262
• 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（由申请方提供）：我们的目的是对儿童期和早发性癌症幸存者的后代进行大规模回顾性队列研究，并确定在试验系统中具有致突变性的治愈性治疗、放疗和化疗导致不良健康结局或其他遗传效应（定义为癌症、出生缺陷、死产、新生儿和所有其他过早死亡）的程度。年轻人的癌症治疗越来越成功。例如，据估计，仅在美国，今天就有超过27万名儿童癌症幸存者，其中许多人能够拥有自己的孩子。因此，癌症幸存者的遗传性疾病的治愈性治疗的可能效果变得越来越重要。然而，人们对这些治疗的遗传后果或潜在的易感性是否会遗传给后代的了解甚少。此外，在20-34岁被诊断患有癌症的年轻人在晚期效应的研究中往往被忽视。虽然几乎没有证据表明诱变疗法会导致跨代效应，但很少有研究关注睾丸或卵巢治疗剂量的风险。丹麦1943年以后和芬兰1952年以后诊断出的35岁以下癌症患者，将与其兄弟姐妹一起沿着进行鉴定。在10 000名活到生育年龄的癌症儿童中，估计有3 000人成为5 600名儿童的父母。在38，000名年轻人被诊断患有癌症的患者中，有25，000人在癌症诊断后存活，并有14，000名儿童。因此，可以研究19，600名癌症幸存者的后代。为了比较的目的，将编制兄弟姐妹及其后代的名册。丹麦和芬兰的后代队列将与结果登记处联系起来，以确定癌症、出生缺陷、死产、新生儿和其他死亡。将获得癌症幸存者的医疗记录，并提取放射记录和化疗信息。将计算性腺（和女性幸存者的子宫）的辐射剂量，并评估治愈性治疗的遗传后果。对于许多癌症幸存者来说，性腺暴露于放射或化疗的程度很高，略低于不孕症的阈值。将从幸存者、其配偶及其后代的样本中采集血液样本，以检查与癌症易感性相关的许多机械过程以及治疗对患者自身及其后代潜在健康结果的影响。200个家庭将捐献淋巴细胞和DMA用于储存和实验室分析，其中包括G2辐射试验，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;评估特定修复基因，如XRCC 1的变异多态性;以及评估小卫星遗传。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。这项研究应该有助于回答有关诱变暴露的遗传后果的问题，探讨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赋予易感性，并评估遗传易感性或遗传损伤可以传递给后代的程度。