文章：

发现癌症易感性基因变异的关联研究

Association studies for finding cancer-susceptibility genetic variants

原文发布日期：2004-11-01

DOI: 10.1038/nrc1476

类型: Review Article

开放获取: 否

要点：

1. The polygenic model for cancer susceptibility indicates that much of the inherited risk of cancer is due to multiple risk alleles, each with a low to moderate risk. The number of such alleles for any specific cancer is unknown, but might be in the hundreds or thousands.
2. Although linkage studies have been highly successful in mapping the genes that underlie monogenic disorders, these studies are of limited use for investigating predisposition to polygenic disease, such as cancer. Genetic-association studies — or case–control studies — provide an efficient design for identifying common genetic variants that confer modest disease risks.
3. Few convincing cancer-susceptibility alleles have been identified so far using the genetic-association study design. The limited success of these studies can be attributed mainly to the use of small study sizes — which provide insufficient statistical power and give a high rate of false positives — and limitations in the selection of candidate genes.
4. The rapid acquisition of data on the occurrence of common single-nucleotide polymorphisms (SNPs) has made it possible to test for the association of a candidate gene or region with disease using a tagging-SNP approach.
5. Several approaches can be used to increase the efficiency of candidate-gene association studies, such as improving the selection of candidate genes that are likely to be associated with cancer predisposition and enriching for genetic susceptibility by studying families with a history of cancer.
6. A combination of cheaper genotyping technologies with efficient study design will make empirical, whole-genome studies a feasible prospect in the near future.
7. Elucidating how multiple susceptibility alleles interact with each other and with lifestyle and environmental factors will be a key future challenge for the molecular and genetic epidemiology of cancer predisposition.

要点翻译：

1. 癌症易感性的多基因模型表明，大部分遗传性癌症风险源于多个风险等位基因，每个等位基因携带低至中度风险。特定癌症的相关等位基因数量尚不明确，但可能达到数百或数千个。
2. 尽管连锁分析在定位单基因疾病相关基因方面成果显著，但这类研究在探究多基因疾病（如癌症）易感性方面作用有限。遗传关联研究——或称病例对照研究——为识别导致轻微疾病风险的常见遗传变异提供了高效方案。
3. 目前通过遗传关联研究设计鉴定的确凿癌症易感性等位基因寥寥无几。这些研究成功率有限的主要原因包括：样本量过小导致统计效力不足和假阳性率高，以及候选基因选择存在局限性。
4. 常见单核苷酸多态性（SNP）数据的快速积累，使得采用标签SNP方法检测候选基因或区域与疾病的关联成为可能。
5. 多种策略可提高候选基因关联研究的效率，例如优化可能关联癌症易感性的候选基因选择，通过研究有癌症家族史的群体来增强遗传易感性富集效果。
6. 更经济的基因分型技术与高效研究设计的结合，将使实证性全基因组研究在不久的将来成为可行前景。
7. 阐明多个易感等位基因之间及其与生活方式、环境因素的相互作用机制，将成为未来癌症易感性分子与遗传流行病学研究的关键挑战。

英文摘要：

Cancer is the result of complex interactions between inherited and environmental factors. Known genes account for a small proportion of the heritability of cancer, and it is likely that many genes with modest effects are yet to be found. Genetic-association studies have been widely used in the search for such genes, but success has been limited so far. Increased knowledge of the function of genes and the architecture of human genetic variation combined with new genotyping technologies herald a new era of gene mapping by association.

摘要翻译： 

癌症是遗传与环境因素复杂相互作用的结果。已知基因仅占癌症遗传力的一小部分，可能还有许多效应微弱的基因尚未被发现。遗传关联研究已被广泛用于寻找此类基因，但迄今为止成效有限。随着基因功能认识的加深、人类遗传变异结构的解析以及新的基因分型技术的出现，基于关联的基因定位正迎来一个崭新的时代。

原文链接：

Association studies for finding cancer-susceptibility genetic variants