Genetic Consequences of Therapies for Cancer

癌症治疗的遗传后果

基本信息

批准号：
7237267
负责人：
JOHN Dunning BOICE
金额：
$ 60.08万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
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/7237267
关键词：
Address Adolescent Age Biochemical Biological Biological Assay Biological Markers Blood Blood specimen Cancer Center Cancer Survivor Cancer Survivorship Cell Cycle Cessation of life Chemical Exposure Chemicals Child Childhood Classification Cohort Studies Conceptions Condition Congenital Abnormality DNA DNA Damage Data Defect Denmark Diagnosis Disease Doctor of Medicine Dose Down Syndrome End Point Epidemiology Evaluation Exposure to Family Female Finland Freezing Frequencies Future Future Generations G2 Phase Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Risk Genetic Variation Genomic Instability Goals Gonadal structure Health Health Status Inborn Genetic Diseases Incidence Individual Infertility Inherited Institute of Medicine (U.S.)Institutes International Investigation Laboratories Late Effects Link Lymphocyte Malignant Childhood Neoplasm Malignant Neoplasms Measures Medical Records Military Personnel Minisatellite Repeats Mutation Neonatal Numbers Occupational Oklahoma Outcome Outcome Study Ovary Parents Patients Persons Pilot Projects Population Predisposition Pregnancy Pregnancy Outcome Process Publications Purpose Radiation Radiation Tolerance Radiation therapy Records Registries Research Research Institute Research Personnel Risk Role Sampling Scientist Siblings Societies Specimen Spouses Survivors System Techniques Testing Testis Text Today Treatment outcome United States Universities Uterus Variant XRCC1 gene abstracting base cancer diagnosis cancer risk cancer therapy chemotherapy child bearing childhood cancer survivor cohort early onset editorial follow-up gene repair genetic association improved interest leukemia neoplasm registry programs repaired repository reproductive response size stillbirth success young adult

项目摘要

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和早发癌症幸存者的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致突变性的治疗性疗法、放疗和化疗的贡献程度不良健康结果或其他遗传效应，定义为癌症、出生缺陷、死产、新生儿和所有其他过早死亡。年轻人的癌症治疗越来越成功。例如，据估计，仅在美国就有超过 270,000 名儿童癌症幸存者今天还活着，其中许多人能够生育自己的孩子。因此，治疗对癌症幸存者遗传性疾病的可能影响变得越来越重要。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知之甚少。此外，在后期影响的研究中，20-34 岁被诊断患有癌症的年轻人经常被忽视。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。 1943 年之后（丹麦）和 1952 年之后（芬兰）所有 35 岁以下被诊断患有癌症的人及其兄弟姐妹都将被识别。在 10,000 名存活至育龄的癌症儿童中，估计有 3,000 名儿童已成为 5,600 名儿童的父母。在 38,000 名年轻时被诊断患有癌症的患者中，有 25,000 人在癌症诊断后存活下来，并育有 14,000 名儿童。因此，可以对 19,600 名癌症幸存者的后代进行研究。将编制兄弟姐妹及其后代的名册以供比较。丹麦和芬兰的后代队列将与结果登记处联系起来，以识别癌症、出生缺陷、死产以及新生儿和其他死亡。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。将计算对性腺（以及女性幸存者子宫）的辐射剂量，并评估治疗疗法的遗传后果。许多癌症幸存者的性腺暴露于放射或化疗的程度很高，略低于不孕的阈值。将从幸存者、其配偶和后代的样本中采集血液样本，以检查与癌症易感性相关的一些机制过程以及治疗对患者本身及其后代潜在健康结果的影响。 200个家庭将捐赠淋巴细胞和DMA用于储存和实验室分析，其中包括G2辐射测定，以评估染色体放射敏感性（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（例如 XRCC1）的变异多态性；和小卫星遗传评估。丹麦的一项试点研究表明，所提出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，探索是否可以识别特定癌症的易感性状态和赋予易感性的特定遗传多态性，并评估所识别的遗传易感性或遗传损伤可以传递给后代的程度。