权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

我们的目的是对儿童期和早发性脑卒中幸存者的后代进行大规模的回顾性队列研究癌症，并确定在何种程度上治愈疗法，辐射和化疗是诱变，测试系统，有助于不利的健康结果或其他遗传效应，定义为癌症，出生缺陷，死胎、新生儿和所有其他过早死亡。年轻人的癌症治疗越来越多，成功例如，据估计，今天在美国有27万多名儿童癌症幸存者。只有国家和许多国家能够有自己的孩子。因此，治愈性治疗的可能效果癌症幸存者遗传性疾病的研究变得越来越重要。然而，这些治疗的遗传后果，或者潜在的易感性是否可以传递给他们，后代此外，20-34岁被诊断患有癌症的年轻人在最近的研究中经常被忽视。方面的影响.虽然几乎没有证据表明诱变疗法会导致跨代效应，但很少有研究表明，研究了睾丸或卵巢的治疗剂量风险。所有35岁以下被诊断患有癌症的人， 1943年在丹麦和1952年后在芬兰将被确定，沿着与他们的兄弟姐妹。在10，000名患有据估计，在存活到生育年龄的癌症患者中，有3，000人已经成为5，600名儿童的父母。之间在38,000名年轻人被诊断患有癌症的患者中，25,000人幸存下来，14,000人在癌症后有了孩子诊断.因此，可以研究19，600名癌症幸存者的后代。兄弟姐妹和他们的后代的名册将是用于比较目的。丹麦和芬兰的后代队列将与结局登记研究相关联确定癌症、出生缺陷、死产、新生儿和其他死亡。癌症幸存者的医疗记录获取放射治疗记录和化疗信息。生殖腺（和子宫）的辐射剂量女性幸存者），并将评估治愈性治疗的遗传后果。性腺许多癌症幸存者的放射或化疗暴露将很高，不孕将从幸存者、他们的配偶和后代的样本中收集血液样本，与癌症易感性和治疗对潜在健康的影响相关的机械过程的数量患者自身及其后代的结果。200个家庭将捐赠淋巴细胞和DMA，储存和实验室分析，包括G2辐射分析，以评估染色体辐射敏感性（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;评估特异性修复基因，如XRCC 1，变异多态性;和评估小卫星传承在丹麦进行的一项试点研究表明，所提出的研究方法是可行的。这项研究应该帮助回答有关诱变暴露的遗传后果的问题，探索易感性是否可以鉴定特定癌症的状态和赋予易感性的特定遗传多态性，并评估经鉴定的遗传易感性或遗传损伤程度可遗传给后代。

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.