Hunter D J, Thomas G, Hoover R N, Chanock S J
Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, MA, USA.
Cancer Causes Control. 2007 Jun;18(5):479-84. doi: 10.1007/s10552-007-0118-y. Epub 2007 Apr 17.
Genome-wide association studies using recently developed large scale single nucleotide polymorphism platforms are beginning to be performed, and results reported. Initial indications are that these studies are capable of discovering loci associated with relative risks too modest to have been detectable through family-based linkage studies. However, as these studies initially test 500,000 or more polymorphisms in a first series of cases and controls, the need for robust replication in one, or preferably, several independent studies is paramount to winnow out the true positive results from the large number of expected false positives. We discuss the need for the formation of consortia to conduct these multi-stage studies, and stress the importance of full disclosure of allele frequencies in cases and controls from these studies in order to facilitate joint analyses across datasets to speed discovery of reproducible associations, and to explore more complex associations such as gene-gene interactions. Desirable characteristics of studies in which genome-wide association studies will be most informative are discussed. The validation of genetic variants that alter risk of specific cancers may be relevant to screening, the identification of high risk persons for risk-reducing interventions, and the discovery of new biological mechanisms that may provide insight into cancer causes and preventive strategies.
利用近期开发的大规模单核苷酸多态性平台进行的全基因组关联研究已开始开展，并报告了相关结果。初步迹象表明，这些研究能够发现与相对风险相关的基因座，而这些风险因过于微小而无法通过基于家系的连锁研究检测到。然而，由于这些研究最初在首批病例和对照中检测50万个或更多的多态性，因此在一项或最好在多项独立研究中进行有力的重复验证对于从大量预期的假阳性结果中筛选出真正的阳性结果至关重要。我们讨论了组建联盟开展这些多阶段研究的必要性，并强调了全面披露这些研究中病例和对照的等位基因频率的重要性，以便促进跨数据集的联合分析，加快发现可重复的关联，并探索更复杂的关联，如基因-基因相互作用。文中还讨论了全基因组关联研究最具信息量的研究的理想特征。改变特定癌症风险的遗传变异的验证可能与筛查、识别可进行降低风险干预的高危人群以及发现可能为癌症病因和预防策略提供见解的新生物学机制有关。
