Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
Br J Cancer. 2010 Jan 19;102(2):428-35. doi: 10.1038/sj.bjc.6605450.
There is a need to develop robust and clinically applicable gene expression signatures. Hypoxia is a key factor promoting solid tumour progression and resistance to therapy; a hypoxia signature has the potential to be not only prognostic but also to predict benefit from particular interventions.
An approach for deriving signatures that combine knowledge of gene function and analysis of in vivo co-expression patterns was used to define a common hypoxia signature from three head and neck and five breast cancer studies. Previously validated hypoxia-regulated genes (seeds) were used to generate hypoxia co-expression cancer networks.
A common hypoxia signature, or metagene, was derived by selecting genes that were consistently co-expressed with the hypoxia seeds in multiple cancers. This was highly enriched for hypoxia-regulated pathways, and prognostic in multivariate analyses. Genes with the highest connectivity were also the most prognostic, and a reduced metagene consisting of a small number of top-ranked genes, including VEGFA, SLC2A1 and PGAM1, outperformed both a larger signature and reported signatures in independent data sets of head and neck, breast and lung cancers.
Combined knowledge of multiple genes' function from in vitro experiments together with meta-analysis of multiple cancers can deliver compact and robust signatures suitable for clinical application.
需要开发稳健且适用于临床的基因表达特征。缺氧是促进实体瘤进展和对治疗产生抗性的关键因素；缺氧特征不仅具有预后价值，还有潜力预测特定干预措施的获益。
我们使用了一种综合基因功能知识和体内共表达模式分析的方法，从三个头颈部和五个乳腺癌研究中定义了一个常见的缺氧特征。先前验证的缺氧调节基因（种子）用于生成缺氧共表达癌症网络。
通过选择在多种癌症中与缺氧种子一致共表达的基因，我们得出了一个常见的缺氧特征或基因集。该基因集高度富集了缺氧调节途径，且在多变量分析中具有预后价值。具有最高连通性的基因也是最具预后价值的，由少数排名靠前的基因组成的简化基因集，包括 VEGFA、SLC2A1 和 PGAM1，在独立的头颈部、乳腺癌和肺癌数据集的验证中，优于更大的特征和已报道的特征。
将体外实验中多个基因功能的综合知识与多个癌症的荟萃分析相结合，可以提供适用于临床应用的紧凑且稳健的特征。
