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Parental genotypes and exposures in sporadic retinoblastoma

散发性视网膜母细胞瘤的父母基因型和暴露

基本信息

批准号：
8090403
负责人：
ARUPA GANGULY
金额：
$ 53.76万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8090403
关键词：
Acute Lymphocytic Leukemia Adult Affect Age Alleles Bilateral Birth Certificates Blood Carcinogens Chemicals Child Childhood Children&apos s Oncology Group Conceptions DNA DNA Damage DNA Repair DNA Repair Gene DNA Repair Pathway Disease Doctor of Philosophy Embryonal Cancers Environmental Exposure Enzyme Gene Enzymes Epidemiologic Studies Etiology Excision Exposure to Eye Family Family history of Fathers Fetus Frameshift Mutation Gene Mutation Gene Proteins Genes Genetic Polymorphism Genomics Genotype Germ Cells Germ-Line Mutation Hospitals Individual Infant Institution Lead Learning Life Life Style Link Malignant Neoplasms Medical Modeling Molecular Mothers Mutagens Mutation Occupational Pathway interactions Point Mutation Predisposition Pregnancy Prevalence RB1 gene Recording of previous events Research Personnel Retina Retinal Retinal Neoplasms Retinoblastoma Risk Role Sporadic Retinoblastomas Spottings Testing Time Tobacco Tumor Suppressor Genes Variant alcohol exposure cancer genetics case control gene repair in utero parental role postnatal precursor cell prenatal programs repaired sperm cell transmission process

项目摘要

DESCRIPTION (provided by applicant): We propose to conduct a molecular epidemiologic study of sporadic retinoblastoma (RB), when it occurs without a family history of the disease. RB, a cancer of the embryonal retina in infants and young children, results from mutation in the RB1 gene and can be bilateral or unilateral. In bilateral RB, the critical mutation occurs almost always on the father's gamete before the child's conception. In unilateral RB, mutation occurs after the child's conception, that is during gestation or early postnatal life. Our model for sporadic RB proposes a role for parental genotypes of carcinogen metabolizing enzymes (CME), DMA repair genes and exposures in determining the risk for a mutation in RB1 gene. The genotype for CME of an individual can influence the level and duration of exposure to a putative carcinogen and the resultant DMA damages. Similarly, the DMA repair genotypes define the efficiency of damage removal, and if not repaired, damages lead to mutations. If the mutation occurs in RB1 gene in a sperm precursor (sporadic bilateral RB) or a developing retinal precursor cell (unilateral RB), retinoblastoma results. For bilateral RB, we hypothesize that polymorphisms in the genes of the father with negative functional consequences increase risk, as do his occupational, dietary, x-ray, tobacco, and alcohol exposures before the child's conception. For unilateral RB, we hypothesize that the polymorphisms in the genes carried by the mother and the child and the exposures during the pregnancy increase risk. The effect of chemical and physical exposures can be specific in that they cause particular types of DNA damages that, if not repaired, lead to particular types of mutations. The mutations in RB1 gene that result in RB can be detected and characterized in a large number of cases. Therefore, we propose to investigate the relationship between specific CMEs, DNA repair pathways, specific exposures, and specific types of RB1 mutations. Cases of unilateral and bilateral RB will be ascertained through the participating hospitals of the Children's Oncology Group, six additional participating centers and Will's Eye Hospital - centers that treat most children with RB in the U.S. Controls will be ascertained through the birth certificates. Case-control comparisons will be made to test hypotheses about polymorphisms in CME and DNA repair genes, and exposures for bilateral and unilateral RB. To test hypotheses about subsets of cases defined by type of RB1 mutation, we will use case-case comparisons. Much has been learned about the mechanism and genetics of cancer from the study of retinoblastoma. We believe the usefulness of retinoblastoma as a paradigm extends to the role of genes other than the disease gene and environmental exposures in childhood and adult cancer.

描述（由申请人提供）：我们建议对散发性视网膜母细胞瘤（RB）进行分子流行病学研究，当它发生时没有家族病史。RB是一种婴幼儿胚胎视网膜癌，由RB1基因突变引起，可为双侧或单侧。在双侧RB中，关键突变几乎总是在孩子受孕前发生在父亲的配子上。在单侧RB中，突变发生在孩子受孕之后，即在妊娠期或产后早期。我们的散发性RB模型提出了致癌物代谢酶（CME）、DMA修复基因和暴露在确定RB1基因突变风险中的亲本基因型的作用。个体CME的基因型可以影响暴露于假定致癌物质的水平和持续时间以及由此产生的DMA损伤。同样，DMA修复基因型决定了损伤去除的效率，如果不修复，损伤就会导致突变。如果RB1基因突变发生在精子前体（散发性双侧RB）或发育中的视网膜前体细胞（单侧RB），则会导致视网膜母细胞瘤。对于双侧RB，我们假设具有负面功能后果的父亲基因多态性增加了风险，就像他在孩子受孕前的职业、饮食、x光、烟草和酒精暴露一样。对于单侧RB，我们假设母亲和孩子携带的基因多态性以及怀孕期间的暴露增加了风险。化学和物理暴露的影响可能是特定的，因为它们会造成特定类型的DNA损伤，如果不加以修复，就会导致特定类型的突变。导致RB的RB1基因突变可以在大量病例中被检测和表征。因此，我们建议研究特定cme、DNA修复途径、特定暴露和特定类型RB1突变之间的关系。单侧和双侧RB病例将通过儿童肿瘤组的参与医院、另外6家参与中心和威尔眼科医院（will’s Eye Hospital）来确定。威尔眼科医院是美国治疗大多数RB儿童的中心。对照病例将通过出生证明来确定。病例对照比较将检验关于CME和DNA修复基因多态性的假设，以及双侧和单侧RB暴露的假设。为了检验由RB1突变类型定义的病例子集的假设，我们将使用个案比较。从视网膜母细胞瘤的研究中，人们对癌症的机制和遗传学有了很多了解。我们认为，视网膜母细胞瘤作为一种范例的有用性延伸到除疾病基因和环境暴露外的基因在儿童和成人癌症中的作用。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mutation spectrum of RB1 gene in unilateral retinoblastoma cases from Tunisia and correlations with clinical features.

DOI：
10.1371/journal.pone.0116615
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Ayari-Jeridi H;Moran K;Chebbi A;Bouguila H;Abbes I;Charradi K;Benammar-Elgaaïed A;Ganguly A
通讯作者：
Ganguly A

Enhanced sensitivity for detection of low-level germline mosaic RB1 mutations in sporadic retinoblastoma cases using deep semiconductor sequencing.

DOI：
10.1002/humu.22488
发表时间：
2014-03
期刊：
HUMAN MUTATION
影响因子：
3.9
作者：
Chen, Zhao;Moran, Kimberly;Richards-Yutz, Jennifer;Toorens, Erik;Gerhart, Daniel;Ganguly, Tapan;Shields, Carol L.;Ganguly, Arupa
通讯作者：
Ganguly, Arupa

Sporadic Retinoblastoma and Parental Smoking and Alcohol Consumption before and after Conception: A Report from the Children's Oncology Group.