Ponder B A J, Antoniou A, Dunning A, Easton D F, Pharoah P D P
Department of Oncology & Public Health & Cancer Research UK Genetic Epidemiology Unit, Strangeways Research Laboratories, University of Cambridge, UK.
Cold Spring Harb Symp Quant Biol. 2005;70:35-41. doi: 10.1101/sqb.2005.70.029.
The known breast cancer predisposing genes account for only about 20% of inherited susceptibility. Epidemiological analyses suggest that much of the remaining 80% is explained by the combined effect of many individually weak genetic variants, rather than by further rare, highly penetrant mutations. In the near term, identification of variants may indicate new pathways or mechanisms in breast cancer development. The polygenic model implies a wide distribution of risk in the population. In the longer term, it may be possible to construct individual risk profiles to guide public health interventions. The search for genetic variants has so far proved difficult. A key unanswered question is the "genetic architecture" of predisposition-that is, strong or weak alleles, common or rare. We describe a genome-wide scan designed to provide a first-pass answer to this question.
已知的乳腺癌易感基因仅占遗传性易感性的约20%。流行病学分析表明，其余80%的大部分是由许多个体效应较弱的基因变异的综合作用所解释，而非由其他罕见的、高外显率的突变所致。在短期内，变异的识别可能会揭示乳腺癌发展中的新途径或机制。多基因模型意味着人群中风险的广泛分布。从长远来看，构建个体风险概况以指导公共卫生干预或许是可行的。迄今为止，寻找基因变异已被证明颇具难度。一个关键的未解决问题是易感性的“遗传结构”——即强或弱等位基因、常见或罕见。我们描述了一项全基因组扫描，旨在为这个问题提供初步答案。
