Parental genotypes and exposures in sporadic retinoblastoma

描述（由申请人提供）：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是婴儿和幼儿的胚胎视网膜癌症，由RB 1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，突变发生在儿童受孕后，即妊娠期间或出生后早期。我们的模型为散发性RB提出了一个作用的父母基因型的致癌物质代谢酶（CME），DMA修复基因和风险，在确定RB 1基因突变的风险。个体的CME基因型可以影响暴露于假定致癌物的水平和持续时间以及由此产生的DMA损伤。类似地，DNA修复基因型定义了损伤去除的效率，如果不修复，损伤会导致突变。如果突变发生在精子前体细胞（散发性双侧RB）或发育中的视网膜前体细胞（单侧RB）的RB 1基因中，则会导致视网膜母细胞瘤。对于双侧RB，我们假设父亲的基因多态性与负面功能后果增加风险，因为他的职业，饮食，X射线，烟草和酒精暴露在孩子的概念。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，因为它们会导致特定类型的DNA损伤，如果不修复，就会导致特定类型的突变。导致RB的RB 1基因突变可以在大量病例中检测和表征。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的RB 1突变之间的关系。单侧和双侧RB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（在美国治疗大多数RB儿童的中心）确定。对照组将通过出生证明确定。将进行病例对照比较，以检验关于CME和DNA修复基因多态性以及双侧和单侧RB暴露的假设。为了检验由RB 1突变类型定义的病例子集的假设，我们将使用病例-病例比较。通过对视网膜母细胞瘤的研究，我们对肿瘤的发生机制和遗传学有了很大的了解。我们相信视网膜母细胞瘤作为一个范例的有用性扩展到基因的作用，而不是疾病基因和环境暴露在儿童和成人癌症。

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.