Genetic Consequences of Therapies for Cancer

癌症治疗的遗传后果

• 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
• 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

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期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诱变性的治疗疗法、放疗和化疗在多大程度上导致不良健康结果或其他遗传效应，如癌症、出生缺陷、死产、新生儿和所有其他过早死亡。对年轻人的癌症治疗越来越成功。例如，据估计，今天仅在美国就有超过27万儿童癌症幸存者活着，其中许多人能够有自己的孩子。因此，治愈性治疗对癌症幸存者遗传性疾病的可能影响正变得越来越重要。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他们的后代知之甚少。此外，在晚期影响的研究中，20-34岁被诊断患有癌症的年轻人往往被忽视。虽然几乎没有证据表明诱变疗法会导致跨代效应，但很少有研究关注治疗剂量对睾丸或卵巢的风险。所有在1943年之后在丹麦和1952年之后在芬兰被诊断为35岁以下癌症的人，以及他们的兄弟姐妹都将被确定。在存活到生育年龄的1万名癌症儿童中，估计有3000人已经成为5600名儿童的父母。在3.8万名年轻时被诊断为癌症的患者中，2.5万名患者存活下来，并在癌症诊断后生下了1.4万名孩子。因此，19,600名癌症幸存者的后代可以被研究。将编制兄弟姐妹及其后代的名册以作比较。丹麦和芬兰的后代队列将与结果登记联系起来，以确定癌症、出生缺陷、死胎、新生儿和其他死亡。获取癌症幸存者的医疗记录，提取放疗记录和化疗信息。将计算对性腺（和女性幸存者的子宫）的辐射剂量，并评估治疗方法的遗传后果。对许多癌症幸存者来说，性腺暴露于辐射或化疗的程度很高，刚好低于不育的阈值。将从幸存者、他们的配偶及其后代的样本中收集血液样本，以检查与癌症易感性相关的一些机制过程，以及治疗对患者本人及其后代的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；对特定修复基因（如XRCC1）的变异多态性进行评估；以及小卫星遗产的评估。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。该研究将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遗传多态性，并评估已确定的遗传易感性或遗传损伤可以遗传给后代的程度。