Parental genotypes and exposures in sporadic retinoblastoma

描述(申请人提供)：我们建议对无家族病史的散发性视网膜母细胞瘤(RB)进行分子流行病学研究。RB是一种婴儿和幼儿的胚胎视网膜癌，由RB1基因突变引起，可以是双侧或单侧的。在双边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，即怀孕或出生后早期。我们的散发性RB模型提出了父母的致癌物代谢酶(CME)、DMA修复基因和暴露在确定RB1基因突变风险中的作用。一个人的CME的基因型别会影响接触一种假定致癌物质的水平和持续时间，以及由此导致的DMA损害。同样，DMA修复基因决定了损伤移除的效率，如果不修复，损伤会导致突变。如果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)中的RB1基因，就会导致视网膜母细胞瘤。对于双边RB，我们假设父亲的基因多态性会增加风险，而父亲在怀孕前的职业、饮食、X光、烟草和酒精暴露也会增加风险。对于单侧RB，我们假设母亲和孩子携带的基因的多态性和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。导致RB的RB1基因突变可以在大量病例中检测到并表现出特征。因此，我们建议调查特定的CME、DNA修复途径、特定的暴露和特定类型的RB1突变之间的关系。单侧和双侧RB的病例将通过儿童肿瘤学小组的参与医院、另外六个参与中心和威尔眼科医院-治疗美国大多数RB儿童的中心-来确定。将进行病例对照比较，以检验关于CME和DNA修复基因的多态以及双侧和单侧RB暴露的假说。为了测试关于由RB1突变类型定义的病例子集的假设，我们将使用病例对病例的比较。从视网膜母细胞瘤的研究中，人们已经了解了许多关于癌症的机制和遗传学的知识。我们认为，视网膜母细胞瘤作为一种范例的用处延伸到儿童和成人癌症中疾病基因和环境暴露之外的基因的作用。

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.