Genetic Consequences of Therapies for Cancer

描述(申请人提供)：我们的目标是对儿童和早发性癌症幸存者的后代进行大规模回溯性队列研究，并确定在测试系统中具有突变性的根治疗法、放射和化疗在多大程度上导致不良健康结果或其他遗传性影响，如癌症、出生缺陷、死产、新生儿和所有其他过早死亡。在年轻人中治疗癌症已经变得越来越成功。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在世，其中许多人能够生下自己的孩子。因此，治疗癌症幸存者遗传性疾病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传染给他们的后代几乎一无所知。此外，在关于晚期效应的研究中，20-34岁被诊断为癌症的年轻人经常被忽视。虽然几乎没有证据表明突变疗法会导致跨代影响，但很少有研究从治疗剂量对睾丸或卵巢的风险方面进行研究。丹麦1943年后和芬兰1952年后所有35岁以下被诊断为癌症的人及其兄弟姐妹都将被识别出来。在存活到育龄的1万名癌症儿童中，据估计有3000名儿童成为了5600名儿童的父母。在38,000名年轻时被诊断为癌症的患者中，有25,000人幸存下来，并在被诊断为癌症后有了14,000个孩子。因此，可以对19,600名癌症幸存者的后代进行研究。为便于比较，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联系起来，以识别癌症、出生缺陷、死产和新生儿及其他死亡。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。将计算对性腺(以及女性幸存者的子宫)的辐射剂量，并将评估根治疗法的遗传后果。对于许多癌症幸存者来说，性腺对放射或化疗的暴露将很高，略低于不孕不育的门槛。血样将从幸存者、他们的配偶和他们的后代中采集，以检查与癌症易感性有关的一些机制过程，以及治疗对患者本身和他们的后代潜在健康结果的影响。200个家庭将捐赠淋巴细胞和DNA用于储存和实验室分析，其中包括G2辐射分析，以评估染色体的辐射敏感性(可能与DMA损伤反应/修复基因的变化有关)，并确定这种敏感性是否可以遗传；评估特定的修复基因，如XRCC1，是否存在变异；以及评估小卫星遗传。丹麦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，探索是否可以确定特定癌症的易感状态和导致易感性的特定基因多态，并评估确定的遗传易感性或遗传损伤可以传递给后代的程度。

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.