Genetic Susceptibility Factors in the Etiology of Neuroblastoma

描述：神经母细胞瘤（NB）是一种周围神经系统肿瘤。它是一种神经嵴细胞衍生物，起源于交感肾上腺谱系，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。NB的早期诊断年龄分布表明，发生在孕前和产前时期的事件可能在这种疾病的发病机制中起重要作用。一些流行病学研究报告说，母亲在怀孕期间使用维生素可以降低NB的风险。NB的胚胎起源和生物学为维生素的病因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-父母三联研究，包括大约1,041例诊断时年龄在5岁以下的NB病例，以评估叶酸、维生素A和相关代谢和转运途径中常见遗传多态性与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。我们将采取综合的方法来选择编码和非编码以及单倍型标记SNP。我们还将评估多个基因对NB风险的联合影响以及基因暴露相互作用对NB风险的影响。叶酸、维生素A和胆碱的摄入将是主要的兴趣。最后，我们将评估NB亚组内的遗传效应，该亚组由诊断时的年龄和基于年龄、MYCN癌基因状态、组织学和DNA倍性的分类模式定义。我们建议招募在三年内诊断的病例及其父母。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。这项研究将涉及从母亲、父亲和NB患儿的DNA收集。将使用经验证的问卷从母亲处获得妊娠期间的膳食和补充维生素摄入量，该问卷使用额外的探针区分母亲的日常饮食与妊娠期间的饮食习惯变化。对于死亡病例，DNA将通过COG神经母细胞瘤生物学方案DNA库提供。神经母细胞瘤有一个独特的年龄发病率和生物学，可能提供深入了解在子宫内起源的儿童癌症。以往的流行病学和生物学研究表明，维生素摄入在预防NB中的作用。以前的研究没有包括这么多的病例，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学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，并且与晚期疾病和治疗相关的发病率越来越相关。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子宫内起源提供线索。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深入了解。这种方法将大大有助于确定维生素关联是否是因果关系。确定神经母细胞瘤的预防因素也是广泛相关的，因为维生素与其他儿童癌症的风险降低有关。

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.