Centre for Population Health Sciences, University of Edinburgh, UK.
J Natl Cancer Inst. 2012 Oct 3;104(19):1433-57. doi: 10.1093/jnci/djs369. Epub 2012 Sep 26.
Colorectal cancer is a major global public health problem, with approximately 950,000 patients newly diagnosed each year. We report the first comprehensive field synopsis and creation of a parallel publicly available and regularly updated database (CRCgene) that catalogs all genetic association studies on colorectal cancer (http://www.chs.med.ed.ac.uk/CRCgene/).
We performed two independent systematic reviews, reviewing 10 145 titles, then collated and extracted data from 635 publications reporting on 445 polymorphisms in 110 different genes. We carried out meta-analyses to derive summary effect estimates for 92 polymorphisms in 64 different genes. For assessing the credibility of associations, we applied the Venice criteria and the Bayesian False Discovery Probability (BFDP) test.
We consider 16 independent variants at 13 loci (MUTYH, MTHFR, SMAD7, and common variants tagging the loci 8q24, 8q23.3, 11q23.1, 14q22.2, 1q41, 20p12.3, 20q13.33, 3q26.2, 16q22.1, and 19q13.1) to have the most highly credible associations with colorectal cancer, with all variants except those in MUTYH and 19q13.1 reaching genome-wide statistical significance in at least one meta-analysis model. We identified less-credible (higher heterogeneity, lower statistical power, BFDP >0.2) associations with 23 more variants at 22 loci. The meta-analyses of a further 20 variants for which associations have previously been reported found no evidence to support these as true associations.
The CRCgene database provides the context for genetic association data to be interpreted appropriately and helps inform future research direction.
结直肠癌是一个全球性的重大公共卫生问题，每年约有 95 万名新患者被诊断出来。我们报告了首例全面的领域概述，并创建了一个平行的、公开的和定期更新的数据库（CRCgene），该数据库对结直肠癌的所有遗传关联研究进行了编目（http://www.chs.med.ed.ac.uk/CRCgene/）。
我们进行了两次独立的系统评价，共查阅了 10 145 篇标题，然后从 635 篇报告 110 个不同基因中的 445 个多态性的出版物中整理和提取数据。我们进行了荟萃分析，得出了 64 个不同基因中的 92 个多态性的汇总效应估计值。为了评估关联的可信度，我们应用了威尼斯标准和贝叶斯假发现概率（BFDP）测试。
我们认为 13 个位点的 16 个独立变体（MUTYH、MTHFR、SMAD7 以及标记 8q24、8q23.3、11q23.1、14q22.2、1q41、20p12.3、20q13.33、3q26.2、16q22.1 和 19q13.1 位点的常见变体）与结直肠癌的关联最可信，除了 MUTYH 和 19q13.1 之外的所有变体在至少一种荟萃分析模型中都达到了全基因组统计学意义。我们还发现了 22 个位点的 23 个可信度较低（异质性较高、统计效力较低、BFDP >0.2）的关联。对先前报道过关联的另外 20 个变体的荟萃分析没有发现证据支持这些真关联。
CRCgene 数据库为遗传关联数据的解释提供了背景，并有助于指导未来的研究方向。
