Genetic Epidemiology of Osteosarcoma

描述（申请人提供）：骨肉瘤（Osteosarcoma， OS）是美国和加拿大20岁以下儿童最常见的骨癌，每年约有430例新诊断病例。骨性骨肉瘤的发病率与儿童期生长曲线密切相关，女性发病高峰较早，且骨性骨肉瘤多发生在腿部长骨，提示小儿骨性骨肉瘤的病因与骨生长有关。这种描述性流行病学的含义是，生长更快速或持续的儿童有更高的OS风险。然而，OS与身高的关系并不一致，与生长有关的其他因素也没有一致的模式。由于青少年骨骼生长的时间和程度受到大量遗传控制，因此对骨肉瘤病因进行遗传调查是适当的。利用儿童肿瘤组（COG）的资源，我们建议进行迄今为止最大和最全面的儿科OS遗传调查。本研究将采用病例-亲本三联体设计，研究与骨骼生长相关的胰岛素样生长因子/生长激素轴和雌激素代谢途径中基因的主要作用，以及涉及DNA完整性的两个基因（RECQL2, RECQL4）。基因x环境（GxE）和基因x基因（GxG）相互作用也将被探讨。常见的单核苷酸多态性（SNP）和其他变异将被选择用于满足以下任何条件的研究：1)在公共数据库中被指定为单倍型标记SNP， 2)编码序列同源算法预测的具有有害功能的非同义SNP， 3)变异对蛋白质功能或表达的影响。大约500名在北美COG机构被诊断为OS的儿童将在三年的时间里与他们的父母一起注册。通过邮件收集口腔细胞进行基因分型；将为少数死亡病例收集储存的血液或组织样本。有关饮食、体育活动、家庭健康史和人体测量的数据也将通过对父母和儿童的邮寄调查收集。

DESCRIPTION (provided by applicant): Osteosarcoma (OS) is the most common bone cancer of children under 20 years of age in the United States and Canada, with about 430 news cases diagnosed each year. The close correlation of OS incidence with the childhood growth curve, the earlier peak in incidence in females, and the frequent occurrence of OS in the long bones of the leg suggest that the etiology of pediatric OS is linked to bone growth. The implication of this descriptive epidemiology is that children with a more rapid or sustained growth spurt have a higher risk of OS. However, the association of OS with height is inconsistent and other factors related to growth have shown no consistent pattern. As the timing and extent of adolescent bone growth are under substantial genetic control a genetic investigation of OS etiology is appropriate. Using the resources of the Children's Oncology Group (COG), we propose to conduct the largest and most comprehensive genetic investigation of pediatric OS to date. This study will employ the case-parent triad design to study main effects of genes in the insulin-like growth factor/growth hormone axis and estrogen metabolism pathways, which relate to bone growth, and two genes involved in DNA integrity (RECQL2, RECQL4). Gene x environment (GxE) and gene x gene (GxG) interaction will also be explored. Common single nucleotide polymorphisms (SNPs) and other variants will be chosen for study that meet any of the following criteria: 1) designation as a haplotype-tagging SNP in public databases, 2) coding non-synonymous SNPs with deleterious function predicted by sequence homology algorithms, 3) effect of variant on protein function or expression reported in the literature. About 500 children diagnosed with OS at North American COG institutions will be enrolled along with their parents over a three-year period. Buccal cells will be collected through the mail for genotyping; stored blood or tissue samples will be collected for the small minority of deceased cases. Data concerning diet, physical activity, family health history, and anthropometries will also be collected through mailed surveys of parents and children.