Jorissen Robert N, Gibbs Peter, Christie Michael, Prakash Saurabh, Lipton Lara, Desai Jayesh, Kerr David, Aaltonen Lauri A, Arango Diego, Kruhøffer Mogens, Orntoft Torben F, Andersen Claus Lindbjerg, Gruidl Mike, Kamath Vidya P, Eschrich Steven, Yeatman Timothy J, Sieber Oliver M
Authors' Affiliations: Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research; Anatomic Pathology Department, Royal Melbourne Hospital, Parkville, Victoria, Australia; Department of Clinical Pharmacology, University of Oxford, Oxford, United Kingdom; Department of Medical Genetics, Biomedicum, University of Helsinki, Helsinki, Finland; Group of Molecular Oncology, Nanomedicine Research Program, Molecular Biology and Biochemistry Research Center (Centro de Investigación Bioquímica y Biología Molecular), Vall d'Hebron Hospital Research Institute, Barcelona, Spain; Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Skejby, Denmark; and GI Surgical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Clin Cancer Res. 2009 Dec 15;15(24):7642-7651. doi: 10.1158/1078-0432.CCR-09-1431.
PURPOSE: Colorectal cancer prognosis is currently predicted from pathologic staging, providing limited discrimination for Dukes stage B and C disease. Additional markers for outcome are required to help guide therapy selection for individual patients. EXPERIMENTAL DESIGN: A multisite single-platform microarray study was done on 553 colorectal cancers. Gene expression changes were identified between stage A and D tumors (three training sets) and assessed as a prognosis signature in stage B and C tumors (independent test and external validation sets). RESULTS: One hundred twenty-eight genes showed reproducible expression changes between three sets of stage A and D cancers. Using consistent genes, stage B and C cancers clustered into two groups resembling early-stage and metastatic tumors. A Prediction Analysis of Microarray algorithm was developed to classify individual intermediate-stage cancers into stage A-like/good prognosis or stage D-like/poor prognosis types. For stage B patients, the treatment adjusted hazard ratio for 6-year recurrence in individuals with stage D-like cancers was 10.3 (95% confidence interval, 1.3-80.0; P = 0.011). For stage C patients, the adjusted hazard ratio was 2.9 (95% confidence interval, 1.1-7.6; P = 0.016). Similar results were obtained for an external set of stage B and C patients. The prognosis signature was enriched for downregulated immune response genes and upregulated cell signaling and extracellular matrix genes. Accordingly, sparse tumor infiltration with mononuclear chronic inflammatory cells was associated with poor outcome in independent patients. CONCLUSIONS: Metastasis-associated gene expression changes can be used to refine traditional outcome prediction, providing a rational approach for tailoring treatments to subsets of patients. (Clin Cancer Res 2009;15(24):7642-51).
目的：目前结直肠癌的预后是通过病理分期来预测的，对于杜克B期和C期疾病的区分能力有限。需要额外的预后标志物来帮助指导个体患者的治疗选择。实验设计：对553例结直肠癌进行了多中心单平台微阵列研究。确定了A期和D期肿瘤之间的基因表达变化（三个训练集），并在B期和C期肿瘤中评估为预后特征（独立测试和外部验证集）。结果：128个基因在三组A期和D期癌症之间显示出可重复的表达变化。使用一致的基因，B期和C期癌症聚为两组，类似于早期和转移性肿瘤。开发了一种微阵列预测分析算法，将个体中期癌症分为A期样/预后良好或D期样/预后不良类型。对于B期患者，D期样癌症患者6年复发的治疗调整风险比为10.3（95%置信区间，1.3 - 80.0；P = 0.011）。对于C期患者，调整后的风险比为2.9（95%置信区间，1.1 - 7.6；P = 0.016）。在一组外部的B期和C期患者中也获得了类似结果。预后特征中免疫反应基因下调，细胞信号和细胞外基质基因上调。因此，在独立患者中，单核慢性炎症细胞的稀疏肿瘤浸润与不良预后相关。结论：转移相关的基因表达变化可用于完善传统的预后预测，为针对患者亚组定制治疗提供合理方法。（《临床癌症研究》2009年；15(24):7642 - 51）
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