Jorissen Robert N, Lipton Lara, Gibbs Peter, Chapman Matthew, Desai Jayesh, Jones Ian T, Yeatman Timothy J, East Philip, Tomlinson Ian P M, Verspaget Hein W, Aaltonen Lauri A, Kruhøffer Mogens, Orntoft Torben F, Andersen Claus Lindbjerg, Sieber Oliver M
Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research, Parkville, Victoria, Australia.
Clin Cancer Res. 2008 Dec 15;14(24):8061-9. doi: 10.1158/1078-0432.CCR-08-1431.
About 15% of colorectal cancers harbor microsatellite instability (MSI). MSI-associated gene expression changes have been identified in colorectal cancers, but little overlap exists between signatures hindering an assessment of overall consistency. Little is known about the causes and downstream effects of differential gene expression.
DNA microarray data on 89 MSI and 140 microsatellite-stable (MSS) colorectal cancers from this study and 58 MSI and 77 MSS cases from three published reports were randomly divided into test and training sets. MSI-associated gene expression changes were assessed for cross-study consistency using training samples and validated as MSI classifier using test samples. Differences in biological pathways were identified by functional category analysis. Causation of differential gene expression was investigated by comparison to DNA copy-number data.
MSI-associated gene expression changes in colorectal cancers were found to be highly consistent across multiple studies of primary tumors and cancer cell lines from patients of different ethnicities (P < 0.001). Clustering based on consistent changes separated additional test cases by MSI status, and classification of individual samples predicted MSI status with a sensitivity of 96% and specificity of 85%. Genes associated with immune response were up-regulated in MSI cancers, whereas genes associated with cell-cell adhesion, ion binding, and regulation of metabolism were down-regulated. Differential gene expression was shown to reflect systematic differences in DNA copy-number aberrations between MSI and MSS tumors (P < 0.001).
Our results show cross-study consistency of MSI-associated gene expression changes in colorectal cancers. DNA copy-number alterations partly cause the differences in gene expression between MSI and MSS cancers.
约15%的结直肠癌存在微卫星不稳定性（MSI）。在结直肠癌中已鉴定出与MSI相关的基因表达变化，但不同特征之间几乎没有重叠，这阻碍了对整体一致性的评估。关于差异基因表达的原因和下游效应知之甚少。
将本研究中89例MSI和140例微卫星稳定（MSS）的结直肠癌以及三篇已发表报告中的58例MSI和77例MSS病例的DNA微阵列数据随机分为测试集和训练集。使用训练样本评估与MSI相关的基因表达变化的跨研究一致性，并使用测试样本将其验证为MSI分类器。通过功能类别分析确定生物途径的差异。通过与DNA拷贝数数据比较来研究差异基因表达的因果关系。
在对来自不同种族患者的原发性肿瘤和癌细胞系的多项研究中，发现结直肠癌中与MSI相关的基因表达变化高度一致（P < 0.001）。基于一致变化的聚类根据MSI状态区分了其他测试病例，个体样本的分类预测MSI状态的灵敏度为96%，特异性为85%。与免疫反应相关的基因在MSI癌症中上调，而与细胞间粘附、离子结合和代谢调节相关的基因下调。差异基因表达被证明反映了MSI和MSS肿瘤之间DNA拷贝数畸变的系统性差异（P < 0.001）。
我们的结果显示了结直肠癌中与MSI相关的基因表达变化的跨研究一致性。DNA拷贝数改变部分导致了MSI和MSS癌症之间基因表达的差异。
