Hypoxia-Driven Gene Expression Is an Independent Prognostic Factor in Stage II and III Colon Cancer Patients

作者：Dekervel Jeroen; Hompes Daphne; van Malenstein Hannah; Popovic Dusan; Sagaert Xavier; De Moor Bart; Van Cutsem Eric; D'Hoore Andr E; Verslype Chris; van Pelt Jos^*

来源：Clinical Cancer Research, 2014, 20(8): 2159-2168.

DOI：10.1158/1078-0432.CCR-13-2958

Purpose: 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.
Experimental Design: 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.
Results: 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).
Conclusions: 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.

• 出版日期2014-4-15