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.

我们的目标是对儿童期和早发型幸存者的后代进行大规模回顾性队列研究癌症并确定治疗方法、放疗和化疗对癌症的致突变性的程度测试系统，导致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。癌症治疗在年轻人中越来越流行成功的。例如，据估计，美国目前仍有超过 270,000 名儿童癌症幸存者只有国家和许多国家能够拥有自己的孩子。因此，治疗的可能效果对癌症幸存者遗传性疾病的研究变得越来越重要。但了解甚少这些治疗的遗传后果或潜在的易感性是否可以传递给他们后代。此外，在最近的研究中，20-34 岁被诊断患有癌症的年轻人经常被忽视。影响。虽然几乎没有证据表明诱变疗法可以导致跨代效应，但很少有研究表明研究了睾丸或卵巢治疗剂量的风险。所有 35 岁以下被诊断患有癌症的人 1943 年在丹麦和 1952 年之后在芬兰以及他们的兄弟姐妹将被确定。在这 10,000 名儿童中据估计，有 3,000 名罹患癌症的人存活到了生育年龄，成为了 5,600 名儿童的父母。之中 38,000 名年轻时被诊断患有癌症的患者中，25,000 人在癌症后存活下来，并育有 14,000 名儿童诊断。因此，可以对 19,600 名癌症幸存者的后代进行研究。兄弟姐妹及其后代的名册将为比较目的而开发。丹麦和芬兰的后代队列将与结果登记相关联识别癌症、出生缺陷、死产以及新生儿和其他死亡。癌症幸存者的医疗记录将被保存获得并提取放射记录和化疗信息。对性腺（和子宫）的辐射剂量女性幸存者）将被计算，并且治疗的遗传后果将被评估。性腺许多癌症幸存者接受放射或化学疗法的程度很高，略低于其阈值不孕症。将从幸存者、他们的配偶和后代的样本中采集血样，以检查与癌症易感性相关的机械过程的数量以及治疗对潜在健康的影响患者本身及其后代的结果。 200个家庭将捐赠淋巴细胞和DMA 储存和实验室分析，其中包括评估染色体放射敏感性的 G2 辐射测定（即可能与 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被继承；评估特定修复基因（例如 XRCC1）的变异多态性；小卫星和评估遗产。丹麦的一项试点研究表明，所提出的研究方法是可行的。研究应该帮助回答有关诱变暴露的遗传后果的问题，探讨易感性是否可以识别赋予特定癌症易感性的状态和特定遗传多态性，并评估确定的遗传易感性或遗传损伤可以遗传给后代的程度。

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

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

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.

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