Genetic Consequences of Therapies for Cancer

癌症治疗的遗传后果

基本信息

批准号：
7682967
负责人：
JOHN Dunning BOICE
金额：
$ 57.34万
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 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7682967
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 Congenital Abnormality DNA DNA Damage DNA Sequence Data Defect Denmark Diagnosis Disease Doctor of Medicine Dose Down Syndrome 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 Occupational Oklahoma Outcome Outcome Study Ovary Parents Patients Persons Pilot Projects Predisposition Pregnancy Pregnancy Outcome Process Publications Radiation Radiation Tolerance Radiation therapy Records Registries Research Research Institute Risk Role Sampling Scientist Siblings Societies Specimen Spouses Survivors System Techniques Testing Testis Text Treatment outcome United States Universities Uterus Variant XRCC1 gene abstracting base cancer diagnosis cancer risk cancer therapy chemotherapy child bearing childhood cancer survivor cohort editorial follow-up gene repair genetic association improved interest leukemia neonatal death neoplasm registry offspring population based premature repaired repository reproductive response stillbirth success young adult

项目摘要

Our objective is to conduct a large-scale retrospective cohort study of the offspring of survivors of childhood and earlyonset 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.

我们的目标是对童年和早期幸存者后代的大规模回顾性队列研究癌症并确定在多大程度的程度测试系统，有助于不良健康结果或其他遗传效应定义为癌症，先天缺陷，死产，新生儿和所有其他早期死亡。年轻人对癌症的治疗已经越来越多成功的。例如，据估计，据估计，超过270,000名儿童癌症幸存者在统一还活着单独的国家和许多人能够有自己的孩子。因此，治愈治疗的可能影响关于癌症幸存者的遗传疾病，越来越重要。但是，几乎没有理解这些治疗的遗传后果，或者是否可以将潜在的易感性传播到其后代。此外，在最近的研究中，经常忽略被诊断为20-34岁的癌症的年轻人效果。虽然几乎没有证据表明诱变疗法会导致跨代作用，但很少有研究从治疗剂量或卵巢的治疗剂量方面看待风险。所有被诊断出患有35岁以下癌症的人 1943年在丹麦和1952年之后，将在芬兰及其兄弟姐妹确定。在10,000名儿童中幸存到生殖年龄的癌症估计有3,000名已成为5,600名儿童的父母。之中 38,000例被诊断为癌症的患者，有25,000名癌症，有14,000名儿童诊断。因此，可以研究19,600个癌症幸存者的后代。兄弟姐妹及其后代将是为了比较而开发。丹麦和芬兰的后代队列将与结果登记处联系在一起为了鉴定癌症，出生缺陷，死产，新生儿和其他死亡。癌症幸存者的病历将获得的以及摘要的辐射记录和化学疗法信息。辐射剂量给性腺（子宫和子宫将计算女性幸存者），并将评估治愈疗法的遗传后果。性腺许多癌症幸存者的放疗或化学疗法的暴露将很高，并且低于阈值不育。血样将从幸存者，他们的配偶和后代的样本中收集与癌症易感性有关的机械过程和治疗对潜在健康的影响患者本身和后代的结果。 200个家庭将捐赠淋巴细胞和DMA 储存和实验室分析将包括G2辐射测定法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继承；评估特定修复基因的变体多态性的特定修复基因；和迷你卫星的评估遗产。丹麦的一项试点研究表明，拟议的研究方法是可行的。该研究应该帮助回答有关诱变暴露的遗传后果的问题，探索是否敏感可以鉴定出特定癌症的状态和特定的遗传多态性，并评估可以将遗传易感性或遗传损害的遗传易感性或遗传损害传播到子孙后代的程度。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Very low-level heteroplasmy mtDNA variations are inherited in humans.

DOI：
10.1016/j.jgg.2013.10.003
发表时间：
2013-12-20
期刊：
JOURNAL OF GENETICS AND GENOMICS
影响因子：
5.9
作者：
Guo, Yan;Li, Chung-I;Sheng, Quanhu;Winther, Jeanette F.;Cai, Qiuyin;Boice, John D.;Shyr, Yu
通讯作者：
Shyr, Yu

Radiotherapy for childhood cancer and risk for congenital malformations in offspring: a population-based cohort study.

DOI：
10.1111/j.1399-0004.2008.01109.x
发表时间：
2009-01
期刊：
Clinical genetics
影响因子：
3.5
作者：
Winther JF;Boice JD Jr;Frederiksen K;Bautz A;Mulvihill JJ;Stovall M;Olsen JH
通讯作者：
Olsen JH

A study of DNA damage recognition and repair gene polymorphisms in relation to cancer predisposition and G2 chromosomal radiosensitivity.

DOI：
10.1002/em.20633
发表时间：
2011-01
期刊：
ENVIRONMENTAL AND MOLECULAR MUTAGENESIS
影响因子：
2.8
作者：
Curwen, Gillian B.;Murphy, Samantha;Tawn, Elizabeth J.;Winther, Jeanette F.;Boice, John D., Jr.
通讯作者：
Boice, John D., Jr.

Comparison of germ line minisatellite mutation detection at the CEB1 locus by Southern blotting and PCR amplification.

通过 Southern blotting 和 PCR 扩增对 CEB1 基因座种系小卫星突变进行比较。

DOI：
10.1093/mutage/geq011
发表时间：
2010
期刊：
Mutagenesis
影响因子：
2.7
作者：
Taylor,Malcolm;Cieslak,Marcin;Rees,GwenS;Oojageer,Anthony;Leith,Cheryl;Bristow,Claire;Tawn,EJanet;Winther,JeanetteF;BoiceJr,JohnD
通讯作者：
BoiceJr,JohnD

Stillbirth, early death and neonatal morbidity among offspring of female cancer survivors.