Authors' Affiliations: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, University Hospitals Leuven; Department of Electrical Engineering (ESAT), STADIUS-iMinds Future Health Department, KU Leuven; Departments of Abdominal Surgical Oncology; Imaging and Pathology, and Clinical Digestive Oncology, University Hospitals Leuven, Leuven, Belgium.
Clin Cancer Res. 2014 Apr 15;20(8):2159-68. doi: 10.1158/1078-0432.CCR-13-2958. Epub 2014 Jan 31.
Hypoxia is considered a major microenvironmental factor influencing cancer behavior. Our aim was to develop a hypoxia-based gene score that could identify high and low risk within stage II and III colon cancer patients.
Differential gene expression of CaCo-2 colon cancer cells cultured in chronic hypoxia versus normoxia was tested for correlation with prognostic variables in published microarray datasets. These datasets were further used to downsize and optimize a gene score, which was subsequently determined in paraffin-embedded material of 126 patients with colon cancer treated in our center.
In the CaCo-2 cells, 923 genes with a 2-fold change and Limma corrected P ≤ 0.0001 were found differentially expressed in hypoxia versus normoxia. We identified 21 genes with prognostic value and overlapping in three different training sets and (n = 224). With a fourth published dataset (n = 177), the six-gene Colon Cancer Hypoxia Score (CCHS) was developed. Patients with low CCHS showed a significant better disease-free survival at three years (77.3%) compared with high CCHS patients (46.4%; log-rank, P = 0.006). This was independently confirmed in an external patient cohort of 90 stage II patients (86.9% vs. 52.2%; P = 0.001).
Hypoxia-driven gene expression is associated with high recurrence rates in stage II and III colon cancer. A six-gene score was found to be of independent prognostic value in these patients. Our findings require further validation and incorporation in the current knowledge on molecular classification of colon cancer.
缺氧被认为是影响癌症行为的主要微环境因素。我们的目的是开发一种基于缺氧的基因评分，以识别 II 期和 III 期结肠癌患者的高风险和低风险。
测试 CaCo-2 结肠癌细胞在慢性缺氧与常氧培养条件下的差异基因表达，以与已发表的微阵列数据集的预后变量相关。这些数据集进一步用于缩小和优化基因评分，然后在我们中心治疗的 126 例结肠癌石蜡包埋标本中确定该评分。
在 CaCo-2 细胞中，发现 923 个基因在缺氧与常氧条件下有 2 倍变化，且 Limma 校正 P ≤ 0.0001，差异表达。我们鉴定出 21 个具有预后价值且在三个不同训练集中重叠的基因（n = 224）。使用第四个已发表的数据集（n = 177），开发了六基因结肠癌缺氧评分（CCHS）。低 CCHS 患者的无病生存率在三年内显著优于高 CCHS 患者（77.3% vs. 46.4%；log-rank，P = 0.006）。这在 90 例 II 期患者的外部患者队列中得到了独立证实（86.9% vs. 52.2%；P = 0.001）。
缺氧驱动的基因表达与 II 期和 III 期结肠癌的高复发率相关。在这些患者中发现了一个六基因评分具有独立的预后价值。我们的研究结果需要进一步验证，并纳入结肠癌分子分类的现有知识中。
