Genetic Susceptibility Factors in the Etiology of Neuroblastoma

描述：神经母细胞瘤是一种周围神经系统的肿瘤。它是起源于交感神经-肾上腺谱系的一种神经脊细胞衍生物，其发育与正常交感神经元的发育有关。它是婴儿期最常见的恶性肿瘤。诊断时的早期年龄分布提示，发生在妊娠前期和产前的事件可能在该病的发病机制中起着重要作用。几项流行病学研究报告称，孕妇在怀孕期间服用维生素可降低罹患NB的风险。NB的胚胎起源和生物学为维生素的病因学作用提供了进一步的证据。我们建议进行一项全国性的病例-父母三合会研究，包括大约1,041例确诊时5岁以下的NB病例，以评估涉及叶酸、维生素A以及相关的代谢和运输途径的常见基因多态与NB风险的独立关联。我们将研究与29个基因(727个SNP)相关的风险。我们将采取综合方法选择编码和非编码以及单倍型标记的SNP。我们还将评估多个基因对NB风险的联合作用以及基因-暴露交互作用对NB风险的影响。叶酸、维生素A和胆碱的摄入量将是主要兴趣所在。最后，我们将评估诊断时年龄和基于年龄、MYCN癌基因状态、组织学和DNA倍体的分类方案定义的NB亚组内的遗传效应。我们建议在三年内登记确诊病例及其父母。病例将通过儿童癌症研究网络确定，这是一个由儿童肿瘤学小组指导的北美儿童癌症登记系统。这项研究将包括从患有NB的母亲、父亲和索引儿童身上收集DNA。怀孕期间的饮食和补充维生素摄入量将从母亲那里获得，使用有效的问卷，使用额外的探测器，以区分母亲在怀孕期间的日常饮食和饮食习惯的变化。对于死亡病例，DNA将通过COG神经母细胞瘤生物学协议DNA库获得。神经母细胞瘤具有独特的年龄-发病率和生物学特性，这可能为儿童癌症的宫内起源提供洞察。以前的流行病学和生物学研究表明，维生素摄入在预防NB中起到了作用。以前的研究没有包括如此多的病例，并广泛调查了遗传易感性在神经母细胞瘤中的作用。对维生素和相关遗传因素的研究将为这种癌症的病因和潜在预防提供重要线索。公共卫生相关性：癌症是儿童死亡的一个重要原因，而且与晚期疾病和治疗相关的发病率日益相关。神经母细胞瘤具有独特的年龄、发病率和生物学特征，这可能为儿童癌症的宫内起源提供线索。我们对基因和基因暴露相互作用的研究提供了对可能预防神经母细胞瘤的维生素途径的洞察。这一方法将极大地帮助确定维生素相关性是否具有因果关系。确定神经母细胞瘤的预防因素也具有广泛的意义，因为维生素与降低其他儿童癌症的风险有关。

DESCRIPTION: Neuroblastoma (NB) is a tumor of the peripheral nervous system. It is a neural crest cell derivative, originating from the sympathoadreanal lineage, and its development is related to that of normal sympathetic neurons. It is the most common malignancy of infancy. The early age at diagnosis distribution of NB suggests that events occurring in the preconceptional and prenatal periods may have an important role in the pathogenesis of this disease. Several epidemiologic studies have reported that maternal use of vitamins during pregnancy reduces the risk of NB. The embryonic origins and biology of NB provide further evidence for an etiologic role for vitamins. We propose to conduct a national case-parent triad study including approximately 1,041 NB cases under the age of 5 years at diagnosis to evaluate the independent association of common genetic polymorphisms involved in folate, vitamin A, and related metabolic and transport pathways with the risk of NB. We will examine the risk associated with 29 genes (727 SNPs). We will take a comprehensive approach to select coding and noncoding and haplotype-tagging SNPs. We will also evaluate the joint effects of multiple genes on the risk of NB and the effects of gene-exposure interactions on the risk of NB. Folate, vitamin A, and choline intake will be of primary interest. Finally, we will evaluate genetic effects within NB subgroups defined by age at diagnosis and a classification schema based on age, MYCN oncogene status, histology, and DNA ploidy. We propose to enroll cases and their parents diagnosed over a three-year period. Cases will be identified via the Childhood Cancer Research Network, a North American childhood cancer registry system directed by the Children's Oncology Group. The study will involve DNA collection from the mother, father, and index child with NB. Dietary and supplemental vitamin intake during pregnancy will be obtained from the mother using a validated questionnaire using additional probes to differentiate the mother's usual diet from dietary habit changes during pregnancy. For deceased cases, DNA will be available via the COG Neuroblastoma Biology Protocol DNA bank. Neuroblastoma has a unique age-incidence and biology that may provide insight into the in utero origins of childhood cancer. Previous epidemiologic and biology studies have suggested the role for vitamin intake in the prevention of NB. No previous study has included this many cases and extensively investigated the role of genetic susceptibility in neuroblastoma. The investigation of vitamins and associated genetic factors will provide important clues to the etiology and potential prevention of this cancer. PUBLIC HEALTH RELEVANCE: Cancer is an important cause of death in children, and increasingly linked with late disease- and treatment-related morbidity. Neuroblastoma has a unique age-incidence and biology that may provide clues to the in utero origins of childhood cancer. Insight into the vitamin pathways that may prevent neuroblastoma is offered by our study of genes and gene-exposure interactions. This approach will significantly help establish whether vitamin associations are causal. The determination of preventive factors for neuroblastoma is also broadly relevant as vitamins have been associated with a reduced risk of other childhood cancers.