Parental genotypes and exposures in sporadic retinoblastoma

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，当它发生时没有该疾病的家族史。 RB 是一种婴儿和幼儿胚胎视网膜癌症，由 RB1 基因突变引起，可以是双侧或单侧。在双侧 RB 中，关键突变几乎总是发生在孩子受孕之前父亲的配子上。在单侧 RB 中，突变发生在孩子受孕后，即妊娠期间或产后早期。我们的散发性 RB 模型提出了致癌物代谢酶 (CME) 的亲本基因型、DMA 修复基因和暴露在确定 RB1 基因突变风险中的作用。个体的 CME 基因型可以影响接触假定致癌物的水平和持续时间以及由此产生的 DMA 损害。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。如果精子前体细胞（散发性双侧 RB）或发育中的视网膜前体细胞（单侧 RB）中的 RB1 基因发生突变，则会导致视网膜母细胞瘤。对于双侧 RB，我们假设父亲基因多态性带来的负面功能后果会增加风险，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会增加风险。化学和物理暴露的影响可能是特定的，因为它们会引起特定类型的 DNA 损伤，如果不修复，就会导致特定类型的突变。在大量病例中可以检测到导致 RB 的 RB1 基因突变并对其进行表征。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、另外六家参与中心和威尔眼科医院（在美国治疗大多数 RB 儿童的中心）进行确定。控制措施将通过出生证明来确定。将进行病例对照比较，以检验有关 CME 和 DNA 修复基因多态性以及双侧和单侧 RB 暴露的假设。为了测试有关由 RB1 突变类型定义的病例子集的假设，我们将使用病例间比较。通过视网膜母细胞瘤的研究，人们对癌症的机制和遗传学有了很多了解。我们相信视网膜母细胞瘤作为范例的有用性扩展到了除疾病基因和环境暴露之外的基因在儿童和成人癌症中的作用。

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.