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Clin Cancer Res. 2014 Apr 15;20(8):2159-68. doi: 10.1158/1078-0432.CCR-13-2958. Epub 2014 Jan 31.

Hypoxia-driven gene expression is an independent prognostic factor in stage II and III colon cancer patients.

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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.



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.

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